Immune imbalance between T helper 1, T helper 17 and regulatory T cells fuels amyotrophic lateral sclerosis pathogenesis: disease trajectory, diagnosis and therapeutic implications

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease, causing motor neuron loss and with limited treatment options. Although traditionally considered non-immune in origin, accumulating evidence implicates the adaptive immune system, particularly CD4⁺ T cell subsets, as key modulators of disease progression. Among these, T helper (Th)1 and Th17 cells are elevated in ALS blood, cerebrospinal fluid and central nervous system tissues, and drive pro-inflammatory cascades. By contrast, regulatory T cells (Tregs) suppress pathogenic inflammation and maintain immune homeostasis; however, in ALS, both Treg number and suppressive function decline, with remaining Tregs showing reduced FOXP3 (the master transcription factor governing Treg function) expression and impaired regulatory capacity. Integrating human and preclinical evidence, we describe how ALS-associated proteins can act as autoantigens that trigger adaptive immune responses, and how Th1/Th17 amplification and Treg insufficiency couple to microglial activation, blood–brain barrier disruption, and motor neuron degeneration, to impact disease trajectory. Convergent signalling pathways and their intersection with metabolic stress provide a mechanistic link between the adaptive immune response and neurodegeneration. We outline biomarker frameworks, spanning immune cell phenotypes, cytokine signatures and transcriptional readouts that define alterations in Th1, Th17 and Treg responses in ALS. Finally, we address the emerging immunomodulatory therapeutic approaches, including the targeted blockade of specific cytokines and signalling pathways, augmentation of Treg number and function, and attenuation of Th1/Th17 activity, while preserving protective Tregs using selective small-molecule approaches. Collectively, the evidence we provide establishes adaptive T cell imbalance as a central, targetable driver of ALS neuroinflammation and provides a rationale for biomarker-guided therapeutics designed to rebalance adaptive immunity and slow disease progression.

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that typically begins in adulthood and often leads to death within three to five years following diagnosis [1–3]. Globally, 1–2 people per 100,000 are diagnosed with ALS each year, with a lifetime risk of approximately 1 in 300 [4, 5]. ALS is the most prominent form of motor neuron disease [4, 6], characterised by the progressive degeneration of upper and lower motor neurons in the brain and spinal cord [7]. Motor neuron degeneration typically begins in limb or bulbar muscles, resulting in muscle weakness and wasting, before spreading to other body regions and eventually ending with respiratory muscle dysfunction [8]. In up to 50% of ALS cases, extra-motor symptoms develop, including behavioural changes, executive dysfunction and language impairment [9]. In 10–15% of cases, symptoms reach a level of severity to fulfil the clinical criteria for frontotemporal dementia, characterised by progressive damage to the frontal and temporal lobes [10].

Over 90% of ALS cases are sporadic with no identifiable genetic cause while the remaining ~ 10% are familial and involve mutations in more than 50 genes [11]. Although many disease-modifying genes have been identified, pathogenic variants in genes encoding Cu/Zn superoxide dismutase (SOD1), transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS) and chromosome 9 open reading frame 72 (C9orf72) proteins occur most frequently [12]. Regardless of aetiology, treatments for ALS are limited, with clinically approved therapies, Riluzole (which dampens glutamate-mediated excitotoxicity) and Edaravone (a free radical scavenger that mitigates oxidative stress) that provide modest improvements and Tofersen (an antisense oligonucleotide targeting SOD1 mRNA) that targets a subset of patients. Furthermore, Edaravone and Tofersen are yet to be approved for ALS in many countries [13, 14]. Therefore, a greater understanding of ALS pathophysiology and the development of novel therapeutic interventions is urgently needed.

ALS pathogenesis is multifactorial and involves coordinated motor neuron-intrinsic stress pathways, including excitotoxicity [15, 16], oxidative stress [17, 18], mitochondrial dysfunction [19, 20], impaired axonal transport [21, 22], RNA binding protein dysfunction [23], and protein aggregation [24], alongside neuronal injury driven by glial cells and peripheral immune responses [25, 26]. Increasingly, neuroinflammation is recognised as a key pathological hallmark of ALS, with activated microglia and astrocytes, blood–brain barrier (BBB) disruption and infiltration of peripheral immune cells contributing to both disease onset and progression [25, 26].

Neuroinflammatory responses in ALS are shaped by extensive involvement of the innate immune system, both in the periphery and central nervous system (CNS). Within the CNS, microglia and astrocytes undergo marked activation and phenotypic shifts, with reactive gliosis consistently reported in ALS human tissue and experimental models [27, 28]. Astrocytes can lose key homeostatic functions, including glutamate uptake and recycling, and acquire neurotoxic properties, thereby amplifying motor neuron vulnerability [29, 30]. Microglia similarly transition toward reactive states associated with increased pro-inflammatory signalling, altered phagocytic activity and impaired homeostatic functions, with current evidence indicating that these phenotypic shifts are stage-dependent across disease progression [31, 32]. Beyond glial responses, complement activation has been implicated in ALS, with aberrant complement signalling proposed to contribute to synapse degeneration and amplification of inflammation within the CNS [33]. In the periphery, alterations in circulating neutrophils, monocytes and natural killer cells have also been observed in ALS cohorts, supporting the concept that systemic immune dysregulation may contribute to disease progression [34]. Notably, large-scale peripheral immune profiling studies have identified broad alterations across both innate and adaptive immune compartments in ALS including, increased frequencies of granulocytes, natural killer cells and multiple leukocyte subsets [35].

Among the adaptive immune cell populations implicated in ALS, T cells have been consistently identified both in ALS post–mortem CNS tissue and animal models, highlighting a potential role for adaptive immunity in modulating neurodegeneration [36–39]. Similar to other neurodegenerative diseases, ALS pathology is marked by glial cell activation and infiltration of peripheral T cells into the CNS, with subsequent release of pro-inflammatory cytokines and neurotoxic molecules [40]. Mutations in ALS-associated genes, such as those encoding SOD1, TDP-43 and C9orf72, can perturb glial homeostatic functions and inflammatory responses, thereby shaping the CNS immune environment and increasing motor neuron vulnerability to inflammation-mediated injury [41–43]. Collectively, these observations support a model in which adaptive immune responses interact dynamically with glial dysfunction and neuron-intrinsic stress pathways to influence disease progression.

T cells are the primary mediators of adaptive immunity and can be classified into different subsets based on their function and the expression of cell surface markers. During thymic selection, thymocytes commit to the CD4⁺ or CD8⁺ lineage and mature into T cells that also express CD3 as part of the T cell receptor complex [44–46]. Within the adaptive immune compartment, CD4⁺ T cells are recognised as key regulators of neuroinflammatory responses and modulators of neurodegeneration in ALS [35, 36, 47, 48]. However, accumulating evidence indicates that other adaptive immune cell populations also contribute to ALS pathogenesis. CD8⁺ T cells are altered in both the peripheral blood and CNS of people living with ALS, with multiple studies reporting increased activation, shifts in effector phenotypes and associations with disease severity and rate of progression [49–52]. Evidence from ALS mouse models further supports a pathogenic role for CD8⁺ T cells, demonstrating CNS infiltration and the capacity to directly promote motor neuron degeneration through interferon gamma (IFN-γ)-induced major histocompatibility complex (MHC) class I upregulation and subsequent engagement of CD8⁺ T cell cytotoxic effector pathways [53, 54].

Emerging evidence also indicates that B cells may contribute to disease progression, with recent studies reporting alterations in peripheral B cell subsets in people living with ALS, including elevated late memory B cells in rapidly progressing and bulbar disease, with higher memory B cell frequencies associated with shorter survival [55]. However, clinical and experimental findings suggest that B cell responses in ALS may be context-dependent rather than uniformly pathogenic, with both neutral and potentially modulatory effects reported across disease stages and model systems [56, 57]. Although multiple adaptive immune populations have been implicated in ALS disease trajectory, accumulating evidence supports a central role for CD4⁺ T cells in coordinating neuroinflammatory responses, which are the focus of this review.

Differentiation of CD4⁺ T cell subsets

CD4⁺ T cells can further differentiate into functionally distinct subsets, including pro-inflammatory T helper (Th)1 and Th17 cells, type 2 immune response promoting Th2 cells, or immunosuppressive regulatory T cells (Tregs). This differentiation is driven by the surrounding cytokine milieu present at the time of activation, which induces lineage-specific transcription factors that shape T cell fate and function [58]. Th1 cells are a subset of conventional CD4⁺ T cells that are important effectors of cell-mediated immunity against intracellular pathogens [59]. Th1 cells develop in the presence of interleukin (IL)-12 or IFN-γ, which activate signal transducer and activator of transcription (STAT)4 or STAT1, respectively, inducing the expression of the transcription factor T-box expressed in T cells (T-bet), encoded by T-box transcription factor 21 (TBX21) [60–62] (Fig. 1). In addition to triggering Th1 differentiation, T-bet can also suppress the development of the opposing Th17 lineage [63]. Th1 cells characteristically express C-X-C motif chemokine receptor (CXCR)3, which facilitates Th1 cell migration toward chemokine (C-X-C motif) ligand (CXCL)9, CXCL10 and CXCL11 cues [64]. Th1 cells secrete high amounts of IFN-γ [65], as well as IL-2, tumour necrosis factor alpha and/or beta (TNF-α/β) [66] and granulocyte-macrophage colony-stimulating factor (GM-CSF).

Fig. 1.

Differentiation of CD4⁺ T cell subsets. Upon binding of the T cell receptor with antigen presented on MHC class II, naive CD4⁺ T cells are activated and can differentiate into various subsets, including T helper (Th) 1, Th17, Th2 and regulatory T cells (Tregs) in response to the cytokine milieu present at the time of activation. Th1 cells, driven by interleukin (IL)-12 and interferon gamma (IFN-γ) via signal transducer and activator of transcription (STAT)4 and STAT1 signalling express the T-box transcription factor T-box expressed in T cells (T-bet). Th1 cells express C-X-C motif chemokine receptor (CXCR)3 and secrete pro-inflammatory cytokines, including IFN-γ, tumour necrosis factor alpha and/or beta (TNF-α/β) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Th17 cells, driven by IL-6, transforming growth factor beta (TGF-β), IL-1β, IL-21 and IL-23 via STAT3 signalling express the transcription factor retinoic acid receptor-related orphan receptor (ROR) gamma t (RORγt). Th17 cells express C-C motif chemokine receptor (CCR)6, secrete IL-17 A and F, IL-21 and GM-CSF, and can convert into ‘ex-Th1’ IFN-γ producing cells following prolonged exposure to IL-12 and/or IL-23. Th2 cells, driven by IL-4 via STAT6 signalling, express the transcription factor GATA binding protein 3 (GATA3). Th2 cells express CCR4 and secrete immunomodulatory cytokines including, IL-4, IL-5 and IL-13. Tregs, driven by IL-2 and TGF-β via STAT5 signalling, express the transcription factor forkhead-box protein 3 (FOXP3). Tregs express ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and programmed death protein 1 (PD-1), and secrete immunosuppressive cytokines, including IL-10, IL-35 and TGF-β, which can suppress pro-inflammatory T cell responses. Dashed black arrow represents Th17 plasticity. Image created with BioRender.com

Th17 cells play a critical role in protection against microbial infections, particularly extracellular bacteria and fungi [67]. Th17 cells develop primarily in the presence of IL-6 and transforming growth factor beta (TGF-β), with IL-21, IL-23 and IL-1β further contributing to their development [68–70] (Fig. 1). These cytokines activate STAT3, inducing the expression of the transcription factor retinoic acid receptor-related orphan receptor (ROR) gamma t (RORγt), encoded by RORC [71, 72]. Th17 cells typically express C-C motif chemokine receptor (CCR)6, which facilitates Th17 cell migration toward chemokine (C-C motif) ligand (CCL)20 cues [73]. Th17 cells predominantly secrete IL-17 A but also produce IL-17 F, IL-21, IL-22 and GM-CSF [74–76]. Notably, TNF-α, which is elevated in ALS serum, cerebrospinal fluid (CSF) and post–mortem spinal cords [77, 78], has also been implicated as a potential driver of Th17 cell polarisation and driver of Treg dysfunction, as observed in other inflammatory contexts such as autoimmune haemolytic anaemia [79]. Moreover, Th17 cells exhibit marked plasticity. Exposure to IL-12 and/or IL-23 induces a STAT4-T-bet-driven transcriptional program which generates a Th1/Th17 intermediate subset (RORγt⁺T-bet⁺) that co-produces IL-17 A and IFN-γ [80]. Sustained IL-12 signalling downregulates RORγt, yielding lineage-traced ‘ex-Th17’ cells that predominantly express T-bet and secrete IFN-γ [81, 82].

Th2 cells are typically involved in protection against extracellular parasitic infections, barrier tissue repair and allergic inflammation [83, 84]. Th2 cells develop in the presence of IL-4, which activates STAT6 to induce the expression of GATA-binding protein 3 (GATA3), the master transcription factor of the Th2 lineage (Fig. 1) [85]. Th2 cells typically express CCR4, which mediates chemotaxis toward CCL17 and CCL22, promoting Th2 localisation to inflamed tissues [86–88]. Th2 cells secrete IL-4, IL-5 and IL-13 [89, 90], which collectively support B cell class switching, eosinophil recruitment and induce alternative (M2-like) macrophage polarisation [91–95]. Further, these Th2-associated cytokines, particularly IL-4, can abrogate Th1- and Th17-driven inflammatory responses by directly suppressing IFN-γ production and by conditioning antigen presenting cells to reduce IL-12 and IL-23 secretion [96–98], thereby limiting Th1 polarisation and IL-23-dependent Th17 responses.

Tregs are essential modulators of immune tolerance and homeostasis. The majority of Tregs are formed in the thymus through positive and negative selection (natural Tregs). However, Tregs can also develop in the periphery from naive CD4⁺ T cells in the presence of TGF-β and IL-2 (induced Tregs), the latter of which activates STAT5 to drive Treg differentiation [99, 100] (Fig. 1). Regardless of their developmental origin, both thymic and peripherally derived Tregs express the transcription factor, forkhead-box protein 3 (FOXP3), which is central to Treg identity and function, and secrete anti-inflammatory cytokines such as IL-10, IL-35 and TGF-β [101–103]. High levels of FOXP3 expression are particularly important for the suppressive capacity of Tregs [104]. Ectonucleotidase triphosphate diphosphohydrolase-1 (CD39), contributes further to Treg-mediated immunoregulation by facilitating the degradation of extracellular ATP and subsequent production of adenosine, thereby reducing pro-inflammatory signalling [105–107]. CD39 activity also promotes Treg stability under inflammatory conditions by preserving FOXP3 expression and preventing phenotypic conversion to pro-inflammatory T cell subsets [107, 108]. In addition, Tregs can modulate immune responses through the expression of immune checkpoint inhibitor programmed death protein 1 (PD-1), which contributes to the suppression of effector T cell activity [109].

T cells in ALS pathogenesis

Upon activation, T cells can extravasate into the CNS where they engage in immunosurveillance [110]. In various CNS pathological conditions, including viral infections, ischemia and multiple sclerosis, T cells and other leukocytes cross the BBB and accumulate within dilated perivascular spaces, subsequently infiltrating the CNS parenchyma [110]. Once within the CNS parenchyma, infiltrating T cells engage with resident microglia, astrocytes and neurons through MHC-peptide recognition and contact-dependent co-stimulation [111, 112]. In parallel, T cell-derived cytokines, including IFN-γ, IL-17 A, TNF-α and GM-CSF, activate glia independent of antigen, promoting pro-inflammatory programs and chemokine release [74, 113]. Specifically, IFN-γ and GM-CSF prime and activate microglia, IL-17 A triggers microglia and astrocytes to produce inflammatory mediators, and activated microglia secrete TNF-α and IL-1β, reinforcing a proinflammatory milieu that amplifies local neuroinflammation [113–116]. In ALS, CXCL10 is detectable in CSF and can be secreted by neurons and microglia under conditions of cellular stress [117]. This indicates that CXCR3 expression equips Th1 cells to home into the CNS, where they can amplify microglial activation and exacerbate BBB dysfunction. Likewise, in other neuroinflammatory settings, activated astrocytes, microglia and barrier endothelial cells secrete CCL20 [118–120], suggesting that CCR6 expression promotes Th17 cells to migrate into the CNS, where they can further drive glial activation and exacerbate BBB dysfunction. Notably, recent research demonstrates that ALS-associated TDP-43 aggregates are taken up by antigen presenting cells, in which the aggregates cause vesicle rupture and promote T cell activation [121]. This evidence provides a direct link between ALS-associated protein aggregation and adaptive immune activation.

In ALS, T cell infiltration has been observed in post–mortem tissue, particularly within the corticospinal tract and ventral horn of the spinal cord, as well as in brain stem motor nuclei and primary motor cortex [37, 39, 122, 123], often with concomitant systemic inflammation. In people living with ALS, several studies employing flow cytometry and single-cell RNA sequencing of blood and CSF reported alterations in peripheral T cell populations. These include increased activated CD4⁺ and CD8⁺ T cells and a reduction in the number of Tregs, collectively indicative of a pro-inflammatory peripheral T cell profile [38, 51, 124]. Complementary immunoassay analyses of serum, CSF and post–mortem spinal cord tissue have demonstrated dysregulated T cell-associated cytokine profiles, with elevated concentrations of IFN-γ, TNF-α, IL-17 A, IL-21, IL-23 and IL-6 [77, 78, 125–127].

Timeline of Th1, Th17 and Treg involvement in ALS

While both CD4⁺ and CD8⁺ T cells infiltrate the CNS in ALS, CD4⁺ Th1, Th17 and Tregs play pivotal, yet distinct, roles in shaping the neuroinflammatory environment of the disease. Th1, Th17 and Treg involvement in ALS pathogenesis follows a dynamic timeline, evolving from pre-symptomatic to late-symptomatic stages of the disease (Table 1). In the pre-symptomatic stage of ALS, before clinical symptoms manifest, there is limited but suggestive evidence of immune system activation. Findings from SOD1^G93A mouse models demonstrate pre-symptomatic infiltration of CD4⁺ T cells into the CNS [36, 47], indicating that the adaptive immune response precedes overt neurodegeneration. During this stage, Th1 and Th17 cells are thought to subtly infiltrate the CNS [128, 129], likely facilitated by Th1/17-associated IFN-γ-, TNF-α- and IL-17 A-induced disruption of tight junctions, leading to BBB dysfunction and increased permeability [130, 131]. However, clear evidence for the pathogenic role of Th1 and Th17 cells at this stage remains limited. Tregs, known for their neuroprotective and anti-inflammatory properties, maintain homeostasis and suppress inflammation during this early phase, potentially delaying disease onset [132, 133] (Fig. 2).

Table 1.

Clinical and experimental evidence for Th1, Th17 and Treg dysregulation in ALS

Evidence Type	Cohort/Model	Compartment/Assay	Key Findings	Clinical/Functional Impact	Ref
Human	Newly diagnosed ALS	Blood and CSF	↑ Activated CD4+ T cells in blood and CSF; activated T cell clonal expansion in CSF; ↑ activated Tregs in blood	High activated CD4+ T cells = reduced survival; high activated Tregs = prolonged survival	[38]
Human	ALS vs. healthy controls	Blood	↑ T-bet+CD4+T cells and ↑IFN-γ+CD4+ T cells	Supports Th1-skewed peripheral immunity in ALS	[126]
Human	ALS vs. healthy controls	Blood ± CSF (sub-cohort)	↑ Th1 and Th17 cells; ↑ Th17:Treg ratio; ↑ IFN-γ; CSF immune changes not consistently observed in smaller sub-cohort	Th1 and Th17 proportions negatively correlate with ALSFRS-R and forced vital capacity	[127]
Human	ALS vs. healthy controls	Serum and CSF	↑ Pro-inflammatory Th1/Th17-associated cytokines including, IFN-γ, TNF-α, IL-6, IL-17 A and IL-23	Supports Th1- and Th17-associated inflammatory milieu in ALS	[77, 78, 125]
Human	Rapid vs. slow progressing ALS	Blood	↓ Tregs, FOXP3 expression, TGF-β and Treg-associated signatures in rapid progression; inverse correlation with disease progression rate	Early low FOXP3 expression predicts future rapid progression and reduced survival	[132]
Human	ALS vs. healthy controls	Blood	↓ Treg suppressive capacity against proliferating effector T cells; Treg suppressive impairment correlates with disease severity and progression rate	Links Treg dysfunction in ALS to worsened disease trajectory	[165]
Human	ALS (longitudinal)	Blood	Treg frequency unchanged; ↓ PD-1+ Tregs; ↑ CD39+ Tregs	Suggests dynamic regulatory/compensatory mechanisms throughout disease progression	[178]
Human	ALS vs. healthy controls	Blood and serum	↑ Th17 cells and Th17:Treg ratio in rapidly progressing ALS; ↑ IL-17 A	Th17 enrichment is associated with rapid progression phenotypes	[167]
Human	ALS vs. healthy controls	Blood	C9orf72 identified as CD4+ T cell autoantigen; ↑ C9orf72-reactive CD4+T cells in ALS; antigen-specific CD4+ T cells secrete IL-5 and IL-10; ↑ IL-10-mediated T cell responses in donors with longer predicted survival time	Evidence for autoimmune component in ALS pathogenesis; suggests balance between pro-inflammatory vs. regulatory cytokine profiles associates with predicted survival	[134]
Human	iPSC-derived motor neurons with or without ALS mutations	Prolonged IFN-γ exposure	TDP-43 mislocalisation/aggregation; p53 pathway activation; ↑ neuronal PD-L1 expression; ALS mutation-dependent neuronal vulnerability	Mechanistic link between Th1 cytokine signalling and motor neuron pathology; PD-L1 proposed as a biomarker of sustained IFN-γ exposure	[152]
Human	iPSC-derived motor neurons and ALS donor-derived Th17 cells	Motor neuron-Th17 cell co-cultures	Th17 cells ↓ motor neuron viability and neurite length; IL-17 A causes dose-dependent neurite degeneration and ↓ neuronal viability	Supports direct IL-17 A neurotoxicity but interpretation of findings caveated by potential alloreactivity in unmatched co-cultures	[169]
Human	ALS-derived TDP-43 aggregates	Antigen presenting cell uptake	TDP-43 aggregates ↑ MHC-dependent Th17 cell activation	Supports aggregate-driven antigen presentation context for Th17 enrichment	[121]
Mouse	Pre-symptomatic SOD1G93A	CNS	CD4+ T cell CNS infiltration prior to symptom onset	Supports early adaptive immune involvement	[36, 47]
Mouse	Early- vs. late-symptomatic SOD1G93A	Spinal cord	Late symptomatic stage: ↑ IFN-γ and T-bet; concomitant ↓ FOXP3 expression and IL-10	Supports a shift toward a Th1-skewed environment with loss of regulatory signatures as disease progresses	[48]
Mouse	SOD1G93A	Treg enrichment/adoptive transfer	Endogenous Tregs protective; adoptive transfer of Treg-enriched CD4+ T cells slowed disease progression rate and prolongs survival	Demonstrates causal neuroprotective role for Tregs in vivo	[48]
Mouse	SOD1G93A	CD4+ T cell adoptive transfer	Endogenous activated Treg and effector T cell subsets both delayed loss of motor function and prolonged survival; Tregs delayed neurological symptom onset; effector T cells slowed progression rate	Supports rational for therapeutic Treg augmentation strategies	[177]
Mouse	SOD1G93A	Spinal cord	Region- and stage-dependent immune signatures; IL-4 mRNA higher early and regionally biased vs. Th1-associated markers	Indicates evolving immune landscape across disease course	[174]
Mouse	SOD1G37R vs. SOD1G93A	Early- and late-onset ALS models	CD4+ T cell aging exacerbates neuroinflammation; ↑ Th1 bias in late-onset model	Supports age-associated Th1 skewing in late-onset ALS context	[146]
Mouse	C9orf72 loss-of-function	Blood and serum	Severe systemic inflammation/autoimmunity; ↑IFN-γ, IL-6, IL-17 A and IL-23	Establishes impaired immune tolerance in C9orf72 deficiency	[143, 144]
Mouse	C9orf72 (myeloid/lymphoid expression)	IL-17 A blockade	C9orf72-linked IL-17 A signalling dysregulated; anti-IL-17 A improves motor function in C9orf72 knockout model	Preclinical support for IL-17 A axis as a tractable therapeutic target	[168]

Abbreviations: ALS Amyotrophic lateral sclerosis, ALSFRS-R ALS Functional Rating Scale-Revised, C9orf72 Chromosome 9 open reading frame 72, CD39 Ectonucleotidase triphosphate diphosphohydrolase-1, CNS Central nervous system, CSF Cerebrospinal fluid, FOXP3 Forkhead-box protein 3, IFN-γ Interferon gamma, IL Interleukin, iPSC Induced pluripotent stem cell, MHC Major histocompatibility complex, PD-1 Programmed death protein 1, PD-L1 Programmed death ligand 1, SOD1 Superoxide dismutase 1, TDP-43 Transactive response DNA-binding protein 43, T-bet T-box expressed in T cells, TGF-β Transforming growth factor beta, Th T helper, TNF-α Tumour necrosis factor alpha, Treg Regulatory T cell, ↑ increase, ↓ decrease

Fig. 2.

Dynamic changes in CD4⁺ T cell subsets across ALS progression. The number and function of T helper (Th) 1, Th17 and regulatory T cell (Treg) populations shift dramatically during the progression of amyotrophic lateral sclerosis (ALS). In early symptomatic stages, Tregs are elevated and functionally suppressive, potentially serving a neuroprotective role. As the disease progresses, Treg number and function decline, marked by a loss of forkhead-box protein 3 (FOXP3) expression. In contrast, pro-inflammatory Th1 and Th17 cells gradually increase over time, reaching peak abundance during late symptomatic stages. These cells are associated with elevated secretion of inflammatory cytokines, including interferon gamma (IFN-γ), interleukin (IL)-17 A and tumour necrosis factor alpha and/or beta (TNF-α/β), which may contribute to neuroinflammation and motor neuron damage. This model highlights a temporal imbalance between pro-inflammatory and regulatory T cell responses that may drive ALS pathogenesis. Image created with BioRender.com

As ALS progresses into the early-symptomatic stage, a shift towards a pro-inflammatory immune profile becomes evident. Increased activation and CNS infiltration of pro-inflammatory Th1 and Th17 cells [127, 129] and a concurrent loss of the number and function of anti-inflammatory Tregs [132], contribute to heightened neuroinflammation and initial motor neuron injury (Fig. 2). Several studies suggest that T cell phenotypes present in both the blood and CSF at this stage are suitable predictors of disease outcomes. In one study, flow cytometric analysis of blood and CSF samples from 89 people newly diagnosed with ALS revealed that a high frequency of activated CD4⁺ T cells in the blood and CSF is associated with poor survival, while a high frequency of activated Tregs in the blood is associated with prolonged survival [38]. This study further demonstrated that activated CD4⁺ and CD8⁺ T cell clones were expanded in the CSF of people with ALS, implying that ongoing adaptive immune responses were present throughout the disease course.

In the advanced-symptomatic stage of ALS, the immune response becomes increasingly dysregulated and damaging. The decline in both the number and suppressive capacity of Tregs reduces the ability of the adaptive immune system to restrain inflammation [132]. Concurrently, Th1 and Th17 cells continue to expand and secrete pro-inflammatory cytokines that perpetuate a neurotoxic environment (Fig. 2) [127]. This highlights the evolving and phase-specific roles of T cell subsets in ALS pathogenesis, from early immune surveillance and homeostatic regulation to late-stage neuroinflammatory amplification.

Building on this concept, recent evidence suggests that ALS pathophysiology encompasses autoimmune-like features. Unlike classical autoimmune neurodegenerative diseases, such as multiple sclerosis or systemic lupus erythematosus, ALS was historically considered to lack a defined autoantigen, with pathology largely attributed to intrinsic neuronal dysfunction, degeneration, and pro-inflammatory glial activation. However, antigen-specific CD4⁺ T cell responses against C9orf72 peptides have now been identified in people with ALS [134]. Notably, C9orf72-reactive CD4⁺ T cell responses were approximately 6-fold greater in individuals carrying expansions in the non-coding regions of C9orf72 than in individuals carrying other ALS mutations, or in those with sporadic ALS with no known mutations [134]. Furthermore, these antigen-specific CD4⁺ T cells were shown to exhibit functional cytokine release, including IFN-γ, IL-5 and IL-10 [134]. The balance between pro-inflammatory and regulatory cytokine profiles also correlated with predicted survival [134], indicating that pro-inflammatory immune responses in ALS are not merely a bystander response but may actively influence disease trajectory. Nevertheless, as these responses were detected post–diagnosis, the temporal relationship to disease onset remains unresolved.

Autoimmunity and immune tolerance dysregulation in ALS

Although ALS displays several autoimmune-like features, the disease does not fall fully within the classical autoimmune spectrum. Neurotoxicity in ALS also arises from neuron-intrinsic stress pathways and glial reactivity, rather than from immune-mediated neurotoxicity alone. This divergence from classical autoimmunity is further underscored by the greater prevalence of ALS in males, contrasting with the strong female bias observed across most autoimmune disorders [135–137]. Moreover, not all ALS-associated gene mutations appear to elicit autoimmunity, indicating that autoreactive CD4⁺ T cell activity likely acts in concert with, rather than independently of, intrinsic neurodegenerative mechanisms. Such interactions may be intensified within IFN-γ-driven inflammatory milieus, where immune activation can exacerbate neuronal vulnerability. Consistent with this, TDP-43 aggregates can prime adaptive immune responses indirectly through danger signal-driven activation, even in the absence of conventional autoantigen presentation [121]. These emerging human-relevant findings highlight the urgent unmet need for longitudinal immune profiling, particularly in familial ALS mutation carriers, in whom pre-symptomatic tracking is feasible. For sporadic ALS, alternative approaches such as prospective immune profiling of peripheral blood and CSF from time of diagnosis or retrospective analyses of biobanked samples are required to infer early immune involvement and define the mechanisms and timeframe for when autoreactive responses arise relative to neurodegeneration.

Building on this, epidemiological evidence supports the existence of autoimmune comorbidity in ALS, while also underscoring key interpretive limitations. In one nested case-control study assessing 43 autoimmune conditions, a prior autoimmune disease diagnosis was associated with a 47% increase in the likelihood of developing ALS, with particularly strong associations reported for conditions including, myasthenia gravis, polymyositis/dermatomyositis, Guillain-Barre syndrome, multiple sclerosis and type 1 diabetes diagnosed before 30 years of age [138]. Importantly, several of these conditions, particularly multiple sclerosis, are characterised by Th1- and Th17-skewed immune responses, raising the possibility that ALS and select autoimmune disorders share partially overlapping pro-inflammatory programs, including Th1/Th17-associated CD4⁺ T cell responses [139–141]. Earlier work similarly reported increased occurrence of autoimmune diagnoses prior to ALS diagnosis, while emphasising caveats such as disease mimicry and limitations inherent to health registry-based analyses [142]. Collectively, these findings support autoimmune-like associations and broader immune dysregulation in ALS, but do not establish ALS as universally autoimmune in origin.

Mechanistic evidence supporting dysregulated immune tolerance is most compelling in genetically defined ALS subsets, particularly those linked to C9orf72. In one study, mice carrying loss-of-function mutations in the C9orf72 ortholog developed severe systemic inflammation alongside widespread autoreactive antibody responses and elevated pro-inflammatory cytokines, including, IFN-γ, IL-6, IL-17 A and IL-23 [143]. These findings were supported by bone marrow transplantation experiments, indicating that haematopoietic C9orf72 deficiency is sufficient to drive systemic autoimmunity and early mortality [143]. In another study, the long isoform of C9orf72 was shown to form a stabilising protein complex with Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8), with loss of SMCR8 function similarly resulting in systemic inflammation and an autoimmune phenotype [144]. However, whether autoimmunity directly contributes to ALS in humans remains unclear. Despite epidemiological associations, a study employing Mendelian randomisation analyses across multiple autoimmune disorders did not identify a strong causal effect of autoimmune disease genetic liability on overall ALS risk [145]. This suggests that shared biology may reflect overlapping inflammatory pathways rather than a universal autoimmune driver of ALS. Collectively, these findings position autoimmunity and impaired immune tolerance as biologically relevant in ALS, particularly in specific genetic contexts, while reinforcing the need for biomarker-guided stratification to define ALS subtypes most likely to exhibit immune-driven disease mechanisms.

Th1 cells in ALS

Clinically, elevated Th1 signatures have been positively correlated with faster ALS progression and worse prognosis [38, 127], supporting a deleterious role for Th1 cells in this disease. In one study, Th1 cells were shown to be increased in the peripheral blood of ALS donors, accompanied by increased expression of T-bet and intracellular IFN-γ [126]. In another study, Th1 cells were increased in the peripheral blood of ALS donors, accompanied by a 2-fold increase in serum IFN-γ concentrations; however, no alterations to the immune profile within the CSF were observed [127]. In this same study, higher frequencies of Th1 cells showed a moderate, negative correlation with both ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity, indicating that increased Th1 responses were associated with greater functional impairment and reduced respiratory capacity [127].

Direct evidence for Th1 involvement in ALS pathogenesis has now been demonstrated, with C9orf72 identified as a target of CD4⁺ T cell autoreactivity. In the study introduced above, C9orf72-derived peptides elicited antigen-specific IFN-γ⁺CD4⁺ Th1-like responses in peripheral blood mononuclear cells from individuals with ALS (n = 28) and healthy controls (n = 28), with overall responses significantly higher in the ALS cohort [134]. Autoreactive responses were detected toward C9orf72 but not SOD1 or TDP-43 peptides [134], consistent with other recent findings showing no significant Th1 response to TDP-43 aggregates [121]. Notably, although individuals with ALS possessed a greater number of C9orf72-reactive T cells overall, this population contained a lower proportion of Th1 cells and an increased proportion of Tregs, relative to healthy controls [134]. These findings may reflect a compensatory expansion of Tregs in response to sustained immune activation. However, as samples were collected after disease onset, it remains unclear whether these immunological changes occur early in disease development or arise secondary to chronic inflammation.

A study by Beers and colleagues found that compared to wild-type mice, mRNA transcript levels for IFN-γ and T-bet were increased in the spinal cords of SOD1^G93A mice, during late symptomatic stages [48]. This was accompanied by reduced FOXP3 and IL-10 mRNA transcript levels, suggesting a shift toward a Th1-skewed environment throughout disease progression that may exacerbate motor neuron vulnerability [48]. A more recent study comparing early-onset SOD1^G93A mice (develop symptoms around 90 days old) and late-onset SOD1^G37R mice (develop symptoms > 270 days old) to wild-type controls reported no change in CD4⁺ T cell subset proportions in early-onset SOD1^G93A mice [146]. In contrast, late-onset SOD1^G37R mice displayed an increased proportion of Th1 cells compared to wild-type mice, indicating an age-associated shift toward a pro-inflammatory adaptive immune profile [146]. This age-associated Th1 bias suggests that prolonged disease course and immune aging may shift the adaptive immune response toward a pro-inflammatory state, positioning Th1 cells as potential amplifiers of late-stage neuroinflammation in ALS.

IFN-γ induces a neurotoxic microglial phenotype, characterised by the secretion of IL-1β, TNF-α and reactive oxygen species, all of which contribute to motor neuron degeneration [147, 148]. IFN-γ also upregulates MHC class II expression on antigen presenting cells, including microglia [149–151], thereby enhancing presentation of ALS-associated peptides to CD4⁺ T cells. This may sustain antigen-specific T cell activation and amplify pro-inflammatory cytokine release, reinforcing a feed-forward inflammatory loop within the CNS. Converging evidence supports a direct pathogenic role for IFN-γ in ALS. In human wild-type induced pluripotent stem cell (iPSC)-derived motor neurons, prolonged IFN-γ exposure elicited ALS-like phenotypes, including cytoplasmic TDP-43 mislocalisation and aggregation, p53-pathway activation and a transition from initial hyperexcitability to loss of electrophysiological function [152]. Notably, iPSC-derived motor neurons carrying the TARDBP^Q331K+/− mutation exhibited a similar level of p53-pathway activation to wild-type neurons even without IFN-γ exposure and did not show TDP-43 pathology under baseline conditions [152]. However, upon IFN-γ exposure, TARDBP^Q331K+/ iPSC-derived motor neurons developed significantly greater TDP-43 mislocalisation than wild-type neurons [152]. Further, this study also demonstrated that prolonged IFN-γ exposure induced a robust upregulation of programmed death ligand 1 (PD-L1) at both RNA and protein levels in wild-type and TARDBP^Q331K+/− motor neurons [152]. Notably, PD-L1 protein expression increased by approximately 5-fold, greatly exceeding levels typically reported in cancer contexts. Together, these findings suggest that Th1 cytokine signalling may function as a pathological trigger that unmasks genetically primed neuronal vulnerability, rather than genetic mutations alone being sufficient to initiate neurodegeneration. Further, these findings highlight excessive neuronal PD-L1 expression as a biomarker of sustained Th1 cytokine exposure in ALS.

In another study, prolonged IFN-γ exposure was also shown to induce neuronal dysfunction in mouse cortical neurons by assembling a neuron-specific IFN-γ receptor-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (GluR1) complex that drives Ca²⁺ influx, nitric oxide production and dendritic damage [153]. In ALS, motor neurons in symptomatic SOD1^G93A mice upregulated the IFN-γ receptor and GluR1 [154], pointing to Th1-driven signalling as a trigger of neuronal vulnerability to degeneration. Conversely, IFN-γ was shown to reduce apoptosis in ALS iPSC-derived motor neurons carrying the FUS^R521H mutation under oxidative stress conditions [155]. Collectively, these findings strengthen the mechanistic link between a Th1-associated cytokine milieu and motor neuron degeneration in ALS. However, IFN-γ may hold a context-dependent, pleiotropic role in disease pathogenesis, with evidence of neurotoxic or neuroprotective actions, depending on conditions.

Elevated concentrations of GM-CSF have been observed in female, but not male, ALS donors [156], a disparity that may be attributed to sex-specific cytokine profiles resulting from estrogen-mediated immune modulation [157, 158]. At sites of inflammation, GM-CSF can be considered pro-inflammatory, facilitating the recruitment and enhanced survival of myeloid cells [159, 160]. Thus, GM-CSF secreted by Th1 or Th17 cells during ALS pathogenesis can further exacerbate neuroinflammation by enhancing microglial activation. Although GM-CSF blockade has not yet been evaluated in ALS, anti-GM-CSF antibody treatment reduced microglial activation and amyloid-β accumulation in Alzheimer’s disease models [161], and has shown therapeutic potential clinically for multiple sclerosis [162].

Supporting a mechanistic link between Th1 neuroinflammation and motor neuron vulnerability, TNF-α potentiated threo-hydroxyaspartate-induced excitotoxic motor neuron degeneration in rat organotypic spinal cord cultures [163]. As a glutamate transport inhibitor, threo-hydroxyaspartate elevates extracellular glutamate and induces excitotoxic stress [15, 16], increasing motor neuron vulnerability to TNF-α-mediated injury. This amplification coincided with elevated extracellular glutamate and oxidative stress, and was abrogated by pharmacological nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibition [163]. Complementing these findings, TNF-α rapidly increased surface expression of Ca²⁺-permeable AMPA receptors on adult spinal motor neurons, thereby increasing neuronal excitotoxic susceptibility [164]. In organotypic spinal cord slices, treatment with a subthreshold TNF-α concentration (6 nM) synergised with modest glutamate-uptake blockade (30 µM pyrrolidine dicarboxylate) to produce marked motor neuron degeneration that was prevented via AMPA receptor blockade [164].

These findings highlight the contribution of Th1 cells in driving neuroinflammation in ALS through direct autoreactive responses against C9orf72, and through cytokine-mediated glial activation and amplification of the inflammatory response. The identification of C9orf72-specific IFN-γ⁺CD4⁺ T cell responses provides direct evidence that Th1 autoreactivity occurs in ALS, supporting earlier associations between elevated IFN-γ and disease progression. However, context-dependent effects, such as IFN-γ-mediated neuronal degeneration or protection, highlight the complexity of Th1 biology and pose challenges for their therapeutic targeting. Notably, much of the current evidence for Th1 involvement stems from cross-sectional blood studies, limiting insight into CNS-specific immune dynamics and highlighting the need for studies incorporating CSF and CNS tissue. While Th1 cells have long been considered central mediators in pro-inflammatory responses, growing evidence points to the Th17 lineage as potent contributors to ALS pathogenesis.

Th17 cells in ALS

Several studies have reported increased proportions of Th17 cells in the peripheral blood, CSF and spinal cord of ALS donors, along with elevated levels of IL-17 A, IL-21 and GM-CSF [77, 126, 156, 165, 166]. In one such study, Th17 cells were increased in the peripheral blood of people with ALS, compared to healthy controls, as shown by increased proportions of CD4⁺IL-17⁺ and CD4⁺IL-21⁺ T cells [126]. Of note, despite the increased proportion of Th17 cells, no significant differences were observed in the expression of RORγt. In a more recent study, Th17 cells were also found to be increased in the peripheral blood of people with ALS, accompanied by increased Th17:Treg ratios. However, concentrations of IL-17 A were not increased and were similar to healthy controls [127]. In this same study, analysis of the immune profile in CSF found no significant changes between ALS and healthy controls, however, this was conducted on a smaller sub-cohort (n = 16 ALS donors and n = 10 healthy controls) than the rest of the study (n = 73 ALS donors and n = 48 healthy controls). Moreover, correlation analysis of findings from this study showed moderate negative correlations between Th17 cell proportions and the ALSFRS-R, as well as forced vital capacity. Collectively, these findings suggest that even in the absence of overt IL-17 A elevation, an increase in Th17 cell numbers, particularly relative to Tregs, may reflect a clinically meaningful pro-inflammatory shift associated with functional decline in ALS.

In a recent clinical study, single-cell RNA sequencing revealed increased frequencies of Th17 cells and increased Th17:Treg ratios in the peripheral blood of people with rapidly progressing ALS [167]. In this study, serum proteomic analyses also revealed increased IL-17 A concentrations in sera of individuals with rapid ALS progression, correlating with the increase in Th17 cells. Notably, discrepancies exist between increased Th17 cell frequencies and IL-17 A concentrations in some studies, potentially reflecting differences in assay sensitivity, patient heterogeneity or Th17 functional plasticity (i.e. conversion to ex-Th17 cells) [82], complicating interpretation of IL-17 A concentrations alone.

In mice, one study demonstrated that a loss-of-function in C9orf72 leads to elevated IL-17 A concentrations in sera and peripheral tissues, and increased Th17 cells in peripheral lymphoid organs [168]. Using bone marrow chimera models, this study also showed that both lymphoid and myeloid intrinsic C9orf72 expression is required to regulate IL-17 A production and the expansion of Th17 cells. Further, mice lacking C9orf72 exhibited increased CNS inflammation and motor deficits, linking Th17 cell dysregulation to neuroinflammation and potential neurodegeneration.

Th17 cells and their signature cytokine IL-17 A have been shown to directly induce motor neuron degeneration in an in vitro human co-culture system utilising iPSC-derived motor neurons and ALS peripheral blood mononuclear cell-derived Th17 cells bearing FUS mutations [169]. Findings from this study showed that ALS Th17 cells partly decreased motor neuron survival and significantly decreased neurite length following a 24-hour co-incubation. Further, this study showed that IL-17 A (5–500 ng) induced concentration-dependent neuronal cell loss and neurite degeneration. Notably, the co-culture system used in this study paired Th17 cells and iPSC-derived motor neurons from different individuals and did not account for genetic variation in MHC and/or other molecules between motor neurons and Th17 cells. Since a core function of T cells is to perform surveillance and react to ‘non-self’ antigens, non-MHC matched pairings can provoke a destructive, alloreactive, pro-inflammatory T cell response, independent of ALS-relevant mechanisms [170]. Therefore, motor neuron degeneration observed in this study may be due to this disparity, with the T cells recognising ‘non-self’ markers rather than being Th17-specific. Future work should employ co-culture systems with matched MHC molecules between cell types, ideally sourcing motor neurons and Th17 cells from the same donor to distinguish specific Th17-mediated effects from non-specific alloreactive responses.

Supporting this design principle, a study in Parkinson’s disease using co-culture models with T cells and iPSC-derived midbrain neurons from the same individual showed that Th17 cells induce death of autologous iPSC-derived neurons via IL-17 A signalling and neuronal NF-κB activation [171]. Although performed in Parkinson’s disease dopaminergic neurons, these findings provide cross-disease mechanistic support for Th17-mediated neurotoxicity and reinforce testing Th17 pathway interventions in ALS. Extending these observations, a recent study using purified ALS donor-derived TDP-43 aggregates showed that aggregates are internalised by antigen presenting cells, disrupt endolysosomal compartments and activate pro-inflammatory T cell responses via antigen presentation [121]. In whole-blood assays, TDP-43 aggregate exposure significantly increased Th17 cell activation, and in antigen presenting cell and T cell co-cultures, T cell activation was MHC-dependent, indicating antigen-specific rather than bystander effects. In situ, imaging mass cytometry of ALS cortex revealed MHC upregulation and found that T cell infiltration co-localised with phosphorylated TDP-43 rich regions [121], supporting a tissue context in which aggregate-driven antigen presentation can recruit Th17 responses. Together, these findings provide a mechanistic bridge between TDP-43 pathology and Th17 enrichment, and position TDP-43 pathology as a plausible upstream driver of Th17-skewing in ALS.

Th2 cells in ALS

Compared to Th1 and Th17 cells, Th2-associated immune signatures remain less extensively characterised in ALS. However, emerging evidence suggests that preservation of Th2-skewed CD4⁺ T cell phenotypes may be associated with a more favourable clinical trajectory. In a longitudinal cohort study incorporating detailed immunophenotyping, increased proportions of Th2-differentiated CD4⁺ central memory T cells were associated with reduced mortality risk in ALS [172]. Notably, this relationship was observed in survival analyses but was not reflected in cross-sectional associations with ALSFRS-R or disease progression rate [172], indicating that Th2-associated profiles may relate more closely to long-term disease outcomes rather than severity at the time of sampling.

Consistent with a potential neuroprotective role for Th2-associated cytokine signalling, IL-4 has been shown to suppress microglia-mediated motor neuron degeneration in vitro, coinciding with reduced microglial production of nitric oxide and superoxide, alongside reduced secretion of pro-inflammatory cytokines such as TNF-α and IL-1β [173]. Th2-associated responses may also contribute to disease stage-dependent shifts in ALS mouse models. In SOD1^G93A mice, spinal cord expression of Th2-associated markers showed clear regional and stage-dependent patterning, with IL-4 mRNA increased early and remaining relatively enriched in the cervical spinal cord compared to lumbar regions across disease progression, contrasting with earlier and more prominent induction of Th1-associated T-bet and IFN-γ in lumbar tissue [174]. This regional bias aligns with a temporally evolving immune landscape in ALS, with early stage immunoregulatory responses transitioning toward a more pro-inflammatory and potentially neurotoxic milieu as disease progresses.

Support for stage-dependent efficacy of Th2-associated signalling has also been reported in vivo. In SOD1^G93A mice, CNS delivery of IL-4 via lentiviral gene therapy altered microglial homeostasis and attenuated the early slowly progressive disease phase, but did not confer benefit in the later, rapidly progressive phase, highlighting that the therapeutic window for IL-4-dependent immunomodulation may be constrained by disease stage [175]. Building on these findings, Th2-associated cytokine signalling may also be integrated within the regulatory arm of the CD4⁺ T cell compartment. In SOD1^G93A mice, FOXP3⁺ Tregs were shown to co-express IL-4 at the single cell level, with an increased proportion of IL-4^highFOXP3⁺ cells compared to wild-type controls [48]. In the same study, adoptive transfer of Treg-enriched CD4⁺CD25⁺ T cells from stable-phase SOD1^G93A mice reduced disease progression rate and extended survival, with IL-4 proposed as a contributing mediator of this outcome [48]. In humans, Th2-associated responses may similarly associate with more favourable disease kinetics, with reduced leukocyte IL-4 and GATA3 expression reported in rapidly progressing ALS and inverse correlations observed between these markers and disease progression rate [132].

Collectively, although the role of Th2 cells in ALS pathogenesis remains underexplored relative to Th1 and Th17 lineages, current evidence supports Th2-associated signalling, particularly IL-4 linked pathways, as a biologically relevant counter-regulatory axis in ALS, capable of modulating microglial activation state and influencing disease trajectory.

Tregs in ALS

Evidence suggests that Treg populations are compromised in ALS, with studies demonstrating that both the number and suppressive function of Tregs are diminished, particularly in those with rapidly progressing disease [132, 176]. Moreover, decreased FOXP3 expression has been observed in ALS, suggesting a direct link between Treg impairment and ALS pathogenesis [165]. In one study, Treg numbers and FOXP3 expression were reduced in rapidly progressing ALS, accompanied by reduced mRNA transcript levels for FOXP3 and TGF-β which were inversely correlated with progression rates [132]. In the same study, a 3.5-year prospective analysis with a second, larger ALS cohort revealed that early reduced FOXP3 levels were predictive of future rapid disease progression and attenuated survival [132]. In contrast to these observations of Treg loss, recent findings indicate that Treg populations may also expand in ALS. In a recent study that identified C9orf72 as a CD4⁺ T cell autoantigen, individuals with ALS exhibited a higher proportion of Tregs and increased numbers of IL-10-producing C9orf72-reactive CD4⁺ T cells compared to healthy controls [134]. These regulatory signatures were associated with reduced Th1 cells and a more favourable predicted survival [134].

Variation in the Treg population throughout the course of disease progression has also been observed in SOD1^G93A ALS mouse models. In one such study, Tregs were increased at early, slow progressing disease stages and were decreased during rapid disease progression with a marked loss in FOXP3 expression [48]. Notably, the adoptive transfer of functional Tregs into these models has been shown to suppress neuroinflammation, delay loss of motor function and neurological symptom onset, and extend survival [177], underscoring the therapeutic potential of Treg modulation.

A recent longitudinal study found that overall Treg numbers remained stable in the blood of individuals with ALS throughout disease progression [178]. However, phenotypic analysis of the Treg population showed a decline in PD-1⁺ Tregs and a concurrent increase in CD39⁺ Tregs [178], with the authors proposing that CD39 upregulation on Tregs may be a compensatory mechanism aimed at mitigating neuroinflammation via enhanced adenosine production. Nevertheless, given the small sample size within this study and lack of supportive functional studies, this notion warrants further investigation.

Therapeutic implications and future directions

The current body of evidence suggests that Th1 and Th17 cells contribute to ALS pathogenesis via a feed-forward loop. After infiltrating the CNS, Th1 and Th17 cells secrete pro-inflammatory cytokines, including IFN-γ, TNF-α and IL-17 A, prime and activate microglia, and drive the release of TNF-α and IL-1β [163, 179] (Fig. 3). In motor neurons, these cytokines trigger NF-κB-dependent stress responses, promote trafficking of Ca²⁺-permeable AMPA receptors and cytotoxicity [153, 164], and with sustained exposure, induce p53-dependent apoptotic pathways [152] (Fig. 3). This pro-inflammatory cytokine milieu can increase BBB permeability [130, 131], upregulate chemokine gradients [113], and further drive Th1/Th17 polarisation. Together, this highlights multiple targets for therapeutic intervention: (i) rebalancing adaptive immunity by dampening Th1/Th17 responses while bolstering Tregs, (ii) inhibiting microglial effector programs (e.g. GM-CSF, TNF-α or NF-κB), (iii) buffering neuronal death programs (e.g. by reducing excitotoxic Ca²⁺ influx and inhibiting p53-driven apoptosis) and (iv) enhancing BBB stability to limit continued T cell CNS infiltration.

Fig. 3.

Mechanisms of Th1 and Th17-driven neuroinflammation and motor neuron degeneration in ALS. Antigen presenting cells internalise antigens, including transactive response DNA-binding protein 43 (TDP-43) aggregates and chromosome 9 open reading frame 72 (C9orf72) peptides, and prime naive CD4⁺ T cells toward T helper (Th)1 and Th17 phenotypes. Th1 and Th17 cells secrete pro-inflammatory cytokines, including interferon gamma (IFN-γ), interleukin (IL)-17 A, tumour necrosis factor alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which activate microglia. Activated microglia amplify inflammation through the secretion of pro-inflammatory cytokines, including IFN-γ, TNF-α and IL-1β, reinforcing a feed-forward loop. These cytokines also act directly on motor neurons: IL-17 A, TNF-α and in some contexts, IFN-γ, induce neuronal nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, whereas IFN-γ, TNF-α and IL-1β signalling engages p53-linked degeneration pathways. Together, these programmes drive motor neuron dysfunction and degeneration with TDP-43 mislocalisation and aggregation. Regulatory T cells (Tregs) suppress pro-inflammatory Th1 and Th17 responses and microglial activation, but their frequency and suppressive capacity declines as ALS progresses. Dashed blue lines represent inhibitory functions. Image created with BioRender.com

While Tregs have emerged as a focal point of immune-based therapeutic strategies in ALS, this emphasis is not arbitrary. Multiple independent studies have demonstrated that higher Treg frequency and preserved suppressive function are associated with slower disease progression and improved survival [132, 165, 176, 178]. However, an exclusive focus on Tregs risks oversimplifying the broader landscape of adaptive immune dysregulation in ALS, particularly given the accumulating evidence that pro-inflammatory Th1 and Th17 subsets actively contribute to neuroinflammation and motor neuron vulnerability. Importantly, Treg dysfunction in ALS likely reflects not only intrinsic defects but also sustained exposure to a cytokine milieu dominated by Th1- and Th17-associated signalling, suggesting that durable immune rebalancing may require simultaneous restraint of pathogenic Th1 and Th17 responses with Treg augmentation strategies [180].

Currently, direct Th1- and Th17-targeting in ALS is limited. While several immune-modifying agents have been evaluated through the HEALY ALS Platform Trial [181], the majority primarily target innate inflammatory or neuroprotective pathways rather than directly modulating Th1/Th17-driven adaptive immune responses and are therefore not discussed in detail here. However, in one recent preclinical study, inhibition of IL-17 A signalling by twice-weekly intraperitoneal injection of a neutralising anti-mouse IL-17 A monoclonal antibody improved motor function in C9orf72 knock out mice [168]. Similar protective effects of IL-17 A neutralisation have been observed in human in vitro Parkinson’s disease co-cultures, where inhibition of IL-17 A signalling with an anti-IL-17 A monoclonal antibody (secukinumab) rescued Th17 cell-induced death of iPSC-derived midbrain neurons [171]. In a pilot ex vivo study using peripheral blood mononuclear cells from sporadic ALS donors, IL-6 receptor blockade with an anti-IL-6 monoclonal antibody (tocilizumab) downregulated SOD1 aggregate-induced inflammatory gene programs and reduced secretion of multiple pro-inflammatory cytokines including, IFN-γ, IL-1β, IL-6 and IL-17 A [182]. These findings provide disease-relevant evidence that IL-6 receptor antagonism can dampen Th17-associated inflammatory responses in ALS, supporting IL-6 signalling as a plausible upstream target for therapeutic T cell modulation. Given the established role of IL-1β in Th17 differentiation, therapeutic targeting of the IL-1 signalling axis has also been evaluated in ALS. In a single-arm pilot clinical study, treatment with the IL-1 receptor antagonist anakinra was found to be safe, well tolerated and was associated with a transient reduction in circulating inflammatory markers during the first ~ 24 weeks [183]. However, no significant slowing of disease progression was observed compared to a matched historical cohort, inflammatory markers increased later in the course of treatment, and anti-drug antibodies developed in most participants [183].

Beyond cytokine targeting, immune modulation strategies that alter CD4⁺ T cell trafficking and activation have also been targeted in ALS. In a randomised placebo-controlled phase 2a clinical trial, treatment with the sphingosine-1 phosphate receptor modulator fingolimod resulted in a marked reduction of circulating CD4⁺ T helper cells relative to CD8⁺ T cells [184]. In this study, whole blood immune gene profiling further showed downregulation of co-stimulatory/activation associated transcripts as well as FOXP3, indicating broad modulation of adaptive immune signalling rather than selective inhibition of a single effector pathway [184]. Notably, direct quantification of Th1 and Th17 subsets was not performed, limiting inference regarding preferential effects on pro-inflammatory versus regulatory adaptive immune compartments.

The Janus kinase/STAT pathway integrates signals from multiple Th1- and Th17-associated cytokines including, IFN-γ, IL-2, IL-6, IL-12 and IL-23 [62], and plays a central role in promoting Th1 differentiation via STAT1/STAT4 activation and stabilising Th17 differentiation through STAT3-dependent signalling [185]. In a recent preclinical study, pharmacological inhibition of Janus kinase signalling with tofacitinib in SOD1^G93A mice showed dose-dependent effects on disease outcomes, with low-dose treatment extending survival and delaying weight loss, whereas higher-dose exposure failed to confer benefit and trended toward causing harm [186]. Notably, survival benefit occurred in the absence of overt motor neuron or neuromuscular junction preservation and was accompanied by broad suppression of inflammatory transcription programs in the spinal cord [186]. Although Th1 and Th17 subsets were not directly quantified, the authors proposed that partial Janus kinase/STAT inhibition may preferentially restrain pathogenic pro-inflammatory T cell responses, whereas more aggressive inhibition may impair Tregs. Together, these findings underscore the importance of dosing and selectivity when attempting to rebalance Th1/Th17-driven neuroinflammation.

Broader immunomodulatory strategies that influence adaptive immune polarisation have also been evaluated in ALS. In a randomised, placebo-controlled phase 2 clinical trial, treatment with Tecfidera, a pleiotropic immunomodulator with established effects on T cell differentiation and inflammatory signalling, resulted in significant lymphopenia, confirming systemic immune engagement [187]. However, treatment with Tecfidera did not slow functional decline or improve respiratory outcomes in ALS and the trial failed to meet both primary and secondary efficacy endpoints [187]. Importantly, Th1- and Th17-specific immune phenotyping was not performed longitudinally, limiting assessment of whether pathogenic pro-inflammatory T cell responses were selectively restrained. Together, these findings suggest that broad immunomodulation alone may be insufficient to counteract established Th1/Th17-driven neuroinflammation in ALS, underscoring the need for strategies that more precisely rebalance pathogenic and regulatory CD4⁺ T cell responses.

While not directly targeting Th1 or Th17 cells, a recent multi-omic study identified the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade as an early, tractable disease pathway in ALS [188], consistent with earlier reports of MAPK over activation and abnormal ERK phosphorylation in ALS models and post–mortem tissue [189]. The MAPK/ERK signalling axis integrates T cell receptor and cytokine signals, and is a key regulator of CD4⁺ T cell fate, promoting Th1 differentiation through IL-2 and IL-12 signalling, while also promoting Th17 cell differentiation via RORγt, IL-21 and IL-23 [190]. Evidence from inflammatory bowel disease further supports this role, with studies in ulcerative colitis and Crohn’s disease showing that pharmacological inhibition of ERK signalling suppresses Th17 differentiation while enhancing Treg expansion under Th17-polarising conditions [191]. In the ALS multi-omic study, pharmacological inhibition of MAPK/ERK kinase (MEK) with trametinib reduced ERK phosphorylation, improved neuronal survival under excitotoxic stress and delayed paralysis onset in female SOD1^G93A mice [188]. Collectively, the evidence links aberrant T cell activation with neurodegeneration and supports MEK/ERK inhibition as a feasible route to rebalance adaptive immune responses.

These findings support inhibition of the Th17 signalling pathway as a viable therapeutic strategy. Nevertheless, the specific pathways by which Th1 and Th17 responses drive ALS pathology remain unresolved. A priority is to delineate the relative contributions of T cell-microglia-mediated signalling versus direct Th1/Th17-induced motor neuron cytotoxicity. To avoid confounding allogeneic T cell response mechanisms of neurodegeneration, co- and tri-culture or organoid models with Th1/Th17 cells, microglia and motor neurons ideally from the same individual or with donor pairs that have matched MHC molecules (as is performed in a donor transplantation setting) will enable these ALS Th1/Th17 specific mechanisms to be identified.

In contrast, due to their immunosuppressive and neuroprotective roles, Tregs have gained traction as a therapeutic target. Two complementary strategies are being tested clinically: (i) pharmacologic Treg expansion with low-dose IL-2 and (ii) adoptive transfer of ex vivo expanded autologous Tregs, typically combined with low-dose IL-2 to support Treg survival and function. Across immune-mediated indications, including graft-versus-host disease [192], ulcerative colitis, Crohn’s disease, rheumatoid arthritis, autoimmune hepatitis [193], and solid organ transplantation [194], early clinical studies report safety and signs of therapeutic benefit using these Treg-based approaches. Likewise, early-phase ALS clinical studies report that both approaches are feasible, safe and well-tolerated, with preliminary evidence for slowed disease progression [195–197]. In a phase 2a clinical trial, three 5-day cycles of low-dose IL-2 selectively expanded peripheral Tregs with a concomitant decrease in plasma CCL2, consistent with an anti-inflammatory shift [198]. In a phase 1 trial, administration of autologous ex vivo expanded Tregs (1 × 10⁶ cells/kg) plus thrice–weekly administration of low dose IL-2 was found to be safe, boosted Treg number and function, and coincided with slowed disease progression and stabilised respiratory capacity [195].

In a subsequent phase 2a trial, monthly autologous Treg infusions (1–3 × 10⁶ cells/kg) with thrice–weekly administration of low-dose IL-2 over 24 weeks was again safe, boosted Treg number and function, and coincided with slowed disease progression in 6/8 participants. However, 2/8 participants with rapidly progressing ALS displayed elevated IL-17 F, oxidised low-density lipoprotein receptor 1 (OLR1) and oxidised low-density lipoprotein (oxLDL) (oxidative stress markers), indicating that this therapeutic strategy is less likely to benefit individuals carrying this biomarker profile [196]. Pharmacometabolomic analysis of ALS plasma samples from this phase 2a trial showed time-dependent metabolic shifts with low-dose IL-2, including a transient rise in kynurenine and alterations in phosphatidylcholines and sphingolipids [199]. Importantly, this study further identified a baseline metabolomic signature predictive of the magnitude of Treg expansion, with lower baseline methionine, sphingomyelin 20:2 and asymmetric dimethylarginine, and higher ether phosphatidylcholine C44:4 and C38:1 indicative of greater Treg expansion [199].

In a recent phase 1 trial, infusion of off-the-shelf, non-MHC matched donor umbilical cord blood Tregs (100 × 10⁶ cells/infusion) administered weekly for four weeks then monthly for 6 months, showed no dose-limiting toxicities and slowed ALS progression [197]. While off-the-shelf non-MHC matched umbilical cord blood Tregs are safe, accessible and cost-effective, persistence of the infused cells is limited due to alloreactive clearance by the adaptive immune system. Repeated dosing can produce meaningful ‘hit-and-run’ immunomodulation, however, pairing this therapy with low-dose IL-2 or antigen-targeting strategies may enhance Treg persistence and functional impact. Nevertheless, collective outcomes from these clinical trials provide evidence for Treg targeted strategies and immune modulation as a therapeutic avenue for ALS.

The identification of actionable immune-linked (Table 2) and other ALS biomarkers, such as OLR1 and oxLDL concentrations and baseline metabolomic signatures, enables stratification of individuals with ALS to predict therapeutic responses and inform optimisation of Treg-based therapies. This precision medicine approach may optimise the efficacy of Treg-based therapies and provide further insight into disease mechanisms. However, a critical challenge in ALS lies in the loss of Treg suppressive function over time, underscoring the need for early and sustained immunomodulation. Additionally, the relative contribution of natural versus induced Tregs throughout ALS progression remains poorly understood. Future studies employing lineage-specific markers (e.g. Helios and neuropilin-1) or single-cell RNA sequencing will be critical for delineating these subsets and determining their respective neuroprotective capacities within the ALS microenvironment.

Table 2.

Actionable immune-linked biomarkers for ALS

Biomarker/Readout	Sample	Assays	aTiming of Measurement	Interpretation	Caveats	Refs
Th17:Treg ratio	Blood ± CSF	Flow cytometry/CyTOF: (CD4+IL-17 A+:CD4+FOXP3+); single cell RNA-sequencing	Baseline; longitudinal (particularly during Treg-based therapy)	↑ Th17:Treg ratio = pro-inflammatory immune skew and worse prognosis	Th17 plasticity: ex-Th17 lose IL-17 A signal; combine with functional Treg assays	[38]
Treg frequency and functional capacity	Blood	Flow cytometry (FOXP3, CD39 and PD-1 expression); in vitro suppression assays	Baseline; longitudinal (particularly during Treg-based therapy)	↑ Frequency and functional capacity = slower ALS progression; candidate identification for Treg-based trials	Activation-induced FOXP3 ≠ lineage stability; consider Helios or Treg-specific demethylated region	[133, 165]
Effector CD4+ T cell frequency	Blood ± CSF	Flow cytometry/CyTOF: (CD4+FOXP3−); single cell RNA-sequencing	At diagnosis; baseline; longitudinal	↑ CD4+FOXP3− frequency = higher mortality risk	Adjust for age, sex and progression rate at time of sampling	[38]
Pro-inflammatory cytokine concentrations (IFN-γ, TNF-α, IL-17 A, GM-CSF, IL-1β, IL-6)	Serum ± CSF	Enzyme-linked immunosorbent assay; meso scale discovery electrochemiluminescence assay; single molecule array	At diagnosis, baseline; longitudinal	↑ Concentrations = active pro-inflammatory milieu	Single-timepoint values vary; readouts can be confounded by infections/co-morbidities	[77, 78, 125–127]
Chemokine concentrations (CCL2, CXCL10)	Serum ± CSF	Enzyme-linked immunosorbent assay; meso scale discovery electrochemiluminescence assay; single molecule array	Baseline; longitudinal (particularly during immune-targeted therapy)	↑ Concentrations = worse clinical metrics and faster ALS progression in some cohorts	Not consistent across studies; assay-dependent readout variability	[166]

Abbreviations: ALS Amyotrophic lateral sclerosis, CCL Chemokine (C-C motif) ligand, CD39 Ectonucleotidase triphosphate diphosphohydrolase-1, CSF Cerebrospinal fluid, CXCL Chemokine (C-X-C motif) ligand, CyTOF Cytometry by time of flight, FOXP3 Forkhead-box protein 3, GM-CSF Granulocyte-macrophage colony-stimulating factor, IFN-γ Interferon gamma, IL Interleukin, PD-1 Programmed death protein 1, Th T helper, TNF-α Tumour necrosis factor alpha, Treg Regulatory T cell, ↑ increase, ↓ decrease

^aTiming definitions: At diagnosis: sample obtained at time of diagnosis; baseline: sample obtained pre-therapeutic intervention; longitudinal: sample obtained throughout therapeutic intervention/disease progression

Looking ahead, chimeric antigen receptor (CAR)-Tregs represent a novel and promising extension of Treg-based immunotherapy in ALS. By engineering Tregs to express CARs that recognise inflammatory cues within the ALS microenvironment, these cells could be redirected to sites of neuroinflammation where their suppressive function is most needed. A basic CAR-Treg design could target MHC class II on activated microglia, which is elevated in ALS spinal cord and motor cortex [200]. However, because MHC class II is broadly upregulated in peripheral inflammation [201, 202], this approach risks non-specific immunosuppression outside of the CNS. A more selective strategy could instead target triggering receptor expressed on myeloid cells 2 (TREM2), which is upregulated on disease-associated microglia in ALS [203, 204]. Yet, even with this enhanced CNS-selective approach, TREM2 expression is also detected on subsets of peripheral macrophages [204] indicating that single-antigen CAR-Tregs may still lack sufficient specificity.

To further restrict Treg activation to ALS-relevant sites of neuroinflammation, a dual CAR system, well established in effector CD4⁺ T cells [205] but not yet applied to Tregs, could be developed. Dual CAR systems express two kinds of CARs within a single cell and require antigen engagement with both CARs to trigger activation of the cell. As an ALS dual CAR-Treg therapeutic approach, the first CAR could be directed against PD-L1, which is markedly upregulated on IFN-γ-stressed motor neurons [152], serving as a trafficking cue to direct CAR-Tregs toward sites of neuronal stress. A second CAR directed against TREM2 would then provide the co-stimulatory signal required for full Treg activation, ensuring suppressive function is only engaged in microenvironments where stressed neurons and disease-associated microglia co-exist. In principle, this dual-target system could shift CAR-Treg therapy from broad immunosuppression toward CNS-specific immune rebalancing, selectively dampening neuroinflammation without suppressing peripheral immunity.

Although CAR-Tregs have not yet been tested in ALS, encouraging results in preclinical autoimmune and clinical transplant settings support their potential to provide targeted, durable immunomodulation [206, 207]. Encouraging first-in-human findings demonstrate favourable safety and biological activity of CAR-Tregs in kidney transplantation [207]. These findings validate targeted CAR-Treg trafficking and activation in humans and provide clinical proof-of-concept for extending antigen-directed Tregs to neuroinflammation in ALS. Furthermore, incorporating orthogonal IL-2/IL-2 receptor pairs in CAR-Tregs can selectively ‘feed’ the engineered cells and enhance their expansion while limiting systemic spillover [208].

Alternatively, borrowing from immune-engineering approaches for cancer treatment to precision tune Tregs in ALS may be a feasible strategy. Using lentiviral transduction [209] or CRISPR/Cas9 [210], homing and retention can be tuned by installing CNS-relevant trafficking molecules (e.g. CXCR3 and CCR6) to target Th1/Th17-mediated inflammation and promote CNS recruitment [211, 212]. Using these methods, Treg lineage stability and suppressive capacity can also be tuned to enforce FOXP3 demethylation [213], co-express FOXP3 with Helios [214], or overexpress CD39 [105]. Moreover, preclinical work indicates that astrocyte targeted IL-2 delivery can expand brain-resident Tregs and attenuate neuroinflammation. In one study, an astrocyte-targeted IL-2 gene delivery system with a small-molecule on-switch was shown to preferentially boost IL-2 production in reactive astrocytes, resulting in selective expansion of CNS resident Tregs and protection against traumatic brain injury, stroke and experimental autoimmune encephalomyelitis in mouse models [215]. Such strategies could overcome limitations associated with impaired Treg function and offer new precision immunotherapy avenues for ALS.

Conclusions

Convergent human and preclinical evidence places CD4⁺ T cell imbalance as a key driver of neuroinflammation in ALS and implies that immune dysregulation is not merely a secondary phenomenon but a key driver of neurodegeneration in this disease. The accumulating evidence indicates that Th1 and Th17 cells contribute to disease progression through chemokine-guided CNS recruitment, antigenic activation from TDP-43 aggregates, and through the secretion of pro-inflammatory cytokines, inducing BBB dysfunction and amplifying microglial activation. In contrast, Tregs exert neuroprotective effects by suppressing their pro-inflammatory counterparts, yet their functional capacity declines as ALS progresses. Critically, evidence for direct Th1 and/or Th17 cell-mediated motor neuron degeneration is limited and context-dependent, underscoring key mechanistic gaps to be addressed.

Translational priorities for future studies are clear. Clinical trials should adopt biomarker-guided stratification (e.g. Th17:Treg ratios, FOXP3 expression profiles and metabolomic signatures) into longitudinal blood and CSF cohorts. Rather than blanket immunosuppression, a logical therapeutic approach involves the selective dampening of Th1/Th17 axes while restoring Treg stability and function. The current most actionable approach involves targeting of Th1 and/or Th17 cells (e.g. via the IL-23/IL-17 A axis, GM-CSF or the STAT-IFN-γ pathway) coupled with Treg augmentation strategies (e.g. low-dose IL-2, adoptive Treg infusion or CAR-Tregs). Further, preclinical studies should also evaluate these immune-targeting approaches in combination with clinically approved ALS therapies (e.g. Riluzole and Edaravone) to assess complementarity and potential synergy. Success of such therapeutic inventions should be defined by convergent readouts, including an immune set-point shift (pro-inflammatory versus homeostatic status), glial quiescence, enhanced neuronal resilience, and measurable improvements in ALS symptoms with slowed disease progression.

Abbreviations

ALS

Amyotrophic lateral sclerosis

ALSFRS-R

ALS Functional Rating Scale-Revised

AMPA

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BBB

Blood–brain barrier

CAR

Chimeric antigen receptor

C9orf72

Chromosome 9 open reading frame 72

CCL

Chemokine (C-C motif) ligand

CCR

C-C motif chemokine receptor

CD39

Ectonucleotidase triphosphate diphosphohydrolase-1

CNS

Central nervous system

CSF

Cerebrospinal fluid

CXCL

Chemokine (C-X-C motif) ligand

CXCR

C-X-C motif chemokine receptor

ERK

Extracellular signal-regulated kinase

FOXP3

Forkhead-box protein 3

FUS

Fused in sarcoma/translocated in liposarcoma

GluR1

Glutamate receptor 1

GM-CSF

Granulocyte-macrophage colony-stimulating factor

IFN-γ

Interferon gamma

IL

Interleukin

IL-1β

Interleukin-1 beta

iPSC

Induced pluripotent stem cell

MAPK

Mitogen-activated protein kinase

MEK

MAPK/ERK kinase

MHC

Major histocompatibility complex

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

OLR1

Oxidised low-density lipoprotein receptor 1

oxLDL

Oxidised low-density lipoprotein

PD-1

Programmed death protein 1

PD-L1

Programmed death ligand 1

ROR

Retinoic acid receptor-related orphan receptor

RORγt

ROR gamma t

SMCR8

Smith-Magenis syndrome chromosomal region candidate gene 8

SOD1

Cu/Zn superoxide dismutase 1

STAT

Signal transducer and activator of transcription

TDP-43

Transactive response DNA-binding protein 43

T-bet

T-box expressed in T cells

TBX21

T-box transcription factor 21

TGF-β

Transforming growth factor beta

Th

T helper

TNF-α

Tumour necrosis factor alpha

TNF-β

Tumour necrosis factor beta

Treg

Regulatory T cell

TREM2

Triggering receptor expressed on myeloid cells 2

Authors’ contributions

C.S. and L.O. conceptualised the review and developed the structure. C.S. performed the literature search, interpreted the evidence, wrote the manuscript, and created all figures and tables. L.O. and R.S. provided critical input on the interpretation of evidence and substantive feedback on manuscript drafts. All authors read and approved the final manuscript.

Funding

Parts of this research were funded by the US Department of Defense Therapeutic Ideas Award AL210095 and the Australian Research Council Centre of Excellence in Quantum Biotechnology CE230100021.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.