T Cells in Systemic Lupus Erythematosus

Introduction

T cells have a central role in SLE pathogenesis. T cell dysregulation affects peripheral tolerance and induces inappropriate activation of B cells^1,2. Various T cell subsets are implicated in disease pathogenesis. These subsets, via excessive production of proinflammatory cytokines and contact-dependent interactions, promote autoantibody production and lead to tissue damage through the recruitment of immune cells. In addition to traditional cytokine signals, several other factors influence T cell dysregulation, including metabolic and epigenetic changes^3,4. In this review, we discuss the function of T cells in SLE, primarily focusing on the various roles of T cell subsets, and how molecular, genetic and epigenetic pathways impact T cell dysregulation. We also address the development of T cell-targeted drugs and their role as potential SLE therapies.

Overview of T cells, T helper subsets and evidence of T cell dysfunction in SLE

CD4+ T helper cells and subsets

T helper cells (Th cells) orchestrate the immune response against pathogens. These cells express CD4 in their surface and are subdivided by cytokine expression profiles, which dictate their subtypes and function in host defense (Figure 1)⁵. The significant plasticity in differentiation and expression of signature cytokines between Th subsets contributes to maintaining the physiologic balance between proinflammatory and anti-inflammatory states. Dysregulated Th responses, with disrupted cytokine homeostasis and predominance of pathogenic Th subsets occur in many autoimmune and inflammatory diseases, including SLE.

Figure 1.

CD4+ T cell subsets relevant in SLE.

• Th1 cells

Th1 cells, classically defined by their production of IL-2 and IFN-γ, are involved in cell-mediated inflammatory responses and defense against intracellular pathogens. Effector Th1 cells express the transcription factor Tbet⁵. Th1 cytokines play central roles in the pathogenesis of SLE. IFN-γ promotes B cell class switching and stimulates pathogenic autoantibody production, at least in part by induction of aberrant Tfh cell activation and germinal center formation⁶. Levels of IFN-γ are elevated in patients with SLE compared to controls and positively correlate with SLE disease activity index (SLEDAI) scores^7,8.

• Th2 cells

Th2 cells play a major role in combating parasitic infections and contribute to atopic conditions. Th2 cells express the GATA3 transcription factor, and their cytokine profile includes IL-4, IL-5, and IL-13. IL-4 promotes B cell differentiation into plasma cells and induces antibody class switching to IgG1 and IgE⁵. In lupus prone mice, blocking IL-4 decreases anti-double-stranded DNA antibodies (anti-dsDNA), whereas administration of IL-4 increases the levels of this autoantibody⁹. However, SLE patients may have a decreased number of IL-4 producing T cells, with the increased IFN-γ/IL-4 CD4+ T cell ratio being positively correlated with SLEDAI scores¹⁰. IL-13 promotes the proliferation and differentiation of B cells, and induces the expression of MHC class II, CD23, and IgE. In addition, IL-13 is a profibrotic cytokine and is a negative regulator of Th17 differentiation¹¹. Previous studies have reported greater levels of circulating IL-13 in patients with SLE^12,13. IL-5 has been traditionally described as a cytokine responsible for stimulating antibody production from activated B cells, and proliferation and differentiation of eosinophils from precursors to mature cells. Although the specific roles of IL-5 in SLE remain to be elucidated, IL-5 is overexpressed in keratinocytes from lesional skin and sera of patients with SLE compared to controls^14,15.

• Th17 cells

Th17 cells are a major source of IL-17, a family of cytokines with potent inflammatory effects and major roles in host defense against extracellular bacteria and fungi. Th17 cells can also exacerbate tissue injury due to the proinflammatory roles of IL-17, including neutrophil recruitment, activation of the innate immune system, and enhancement of B cell functions. The Th17 phenotype is regulated by the RORγt and RORα, which are induced by TGFβ and IL-6 in a STAT3-dependent manner⁵.

Several studies have demonstrated a central role of Th17 cells and IL-17 in SLE pathogenesis. IL-17 and B-cell activating factor (BAFF) could have a synergistic effect at enhancing B cell differentiation, proliferation and antibody production¹⁶. Moreover, IL-17 levels correlate with SLEDAI scores, and baseline levels are higher in patients with persistently active nephritis despite therapy^17,18. Similarly, IL-23, which is required for Th17 maintenance, is elevated in patients with SLE compared to controls, and high levels are associated with renal involvement¹⁹. In patients with active lupus nephritis, IL-23 levels were higher in those who did not respond to therapy compared to partial or complete responders¹⁸. In murine lupus, mice deficient in the IL-23 receptor have lower anti-dsDNA levels and less severe nephritis²⁰.

• Th 22 cells

Th22 cells predominantly produce IL-22, a member of the IL-10 family that is thought to play a role in protective immunity, limiting local intestinal and liver inflammation, as well as systemic inflammatory responses²¹. However, pathogenic roles of IL-22 have been reported in psoriasis and rheumatoid arthritis. The specific role of this cytokine in SLE remains controversial due to conflicting data and the potential for anti-inflammatory or pro-inflammatory functions depending on the microenvironment^22,23.

Previous studies have shown that patients with SLE have a greater proportion of Th22 cells when compared to healthy controls. Similarly, a positive correlation between Th22 cells and IL-22 plasma concentration in SLE patients, as well as between the percentage of Th22 cells and SLEDAI scores have also been described^17,22,24. Conversely, other studies have shown reduced levels of circulating IL-22 or IL-22-producing cells in active SLE patients compared to inactive SLE patients and healthy controls, as well as an inverse correlation between SLEDAI scores and IL-22 levels^23,25–27. The conflicting results among different studies are possibly due to timing of evaluation with respect to disease course, medication use, or clinical phenotype. For example, a study assessing new-onset SLE patients found decreased plasma levels of IL-22 compared to relapsing SLE patients, which increased after improved disease activity and treatment with hydroxychloroquine and systemic steroids²³. Moreover, IL-22 levels are increased in SLE patients with sole skin involvement and decreased in those with only lupus nephritis¹⁷. Patients with class III or class IV lupus nephritis were also shown to have significantly lower levels of urinary IL-22 mRNA than those with class V nephritis²⁸.

• Th9 cells

Although originally classified as a Th2 cytokine, IL-9 is now thought to be mainly produced by a distinct subset identified as Th9 cells. Interferon Regulatory Factor 4 (IRF4) is crucial for IL-9 production and Th9 development²⁹. IL-9 acts in multiple cells as a growth factor, including mast cells and eosinophils. This cytokine also plays a central role in allergic airway disease, tumor immunity, and inflammatory bowel disease, although anti-inflammatory functions have also been described²⁹. In lupus-prone mice, IL-9 has been implicated in B cell activation, proliferation and heightened autoantibody production, and improved nephritis outcomes when the mice are treated with IL-9 neutralizing antibodies³⁰. However, only a few studies have assessed the role of Th9 and IL-9 in patients with SLE, suggesting elevated circulating levels of this cytokine when compared to healthy controls. Whether IL-9 and Th9 frequency are associated with SLE-specific characteristics is less clear³¹.

• Regulatory T cells (Treg)

Treg are crucial in maintaining self-tolerance and immune homeostasis. These cells are characterized by expression of the IL-2 receptor alpha chain (CD25) and the nuclear transcription factor FoxP3. Treg also express CTLA4, and the transcription factors Neuropilin-1 and Helios³². These cells suppress activation and expansion of auto-reactive lymphocytes, and thus are crucial in maintaining peripheral tolerance to self antigens. Tregs have been further subdivided according to their developmental origin into thymic Treg and peripherally-induced Treg³². No protein markers have been identified to date to accurately distinguish between these two populations of Treg, although there are important epigenetic differences³³.

Although both quantitative and qualitative differences in Treg have been described in SLE, studies to date have shown contradictory results^34,35. The selection of phenotypic markers to characterize the Treg population, the protocols used for isolation and stimulation of these cells, as well as the SLEDAI thresholds to differentiate between active and inactive SLE have potentially played a role in these discrepancies³⁶. It is also possible that the number and function of Treg are not uniformly affected in all SLE patients or that other mechanisms, such as an acquired resistance of effector T cells to suppression by Tregs may be involved³⁷.

• T follicular helper cells (Tfh)

Tfh localize in germinal centers and extrafollicular foci, providing B cells with key survival, differentiation and maturation signals. The transcription factor BCL6 is required for Tfh development³⁸. In the normal immune response, the main role of Tfh cells is to assist B cells during the response to T cell dependent antigens, by releasing cytokines such as IL-21 and IL-4. SLE-specific autoantibodies such as anti-dsDNA acquire high antigen affinity through somatic hypermutation, indicating Tfh involvement in generating autoreactive B cell clones in both murine and human SLE³⁹. In lupus nephritis, Tfh aggregate in renal tissue with B cells, similar to what is observed in germinal centers⁴⁰. Contact-dependent molecules such as CD40L and ICOS from Tfh also enhance activation of B cells in murine models of autoimmunity⁴¹.

Therefore, cognate T-B cell interactions are crucial in the development and maintenance of self-reactive B cells and their differentiation into autoantibody-producing plasma cells.

CD8 T cells

CD8 T cells recognize peptide antigens presented by MHC class I molecules and their main effector function consists of the release of perforin and granzymes⁴². These cells participate in infection control, anti-tumoral response, and autoimmunity. Circulating CD8 T cells from patients with SLE display functional defects including impaired cytolytic function with decreased production of granzyme and perforin⁴³. An exhausted phenotype in circulating CD8 T cells from patients with SLE has been associated with lower disease flare rates⁴⁴. These qualitative abnormalities in CD8 T cells may contribute to the pathogenesis of autoimmunity in SLE and likely relate to the predisposition of patients with SLE to infections, which can be further exacerbated by the use of immunosuppressive drugs⁴⁵.

In mice with lupus-like nephritis, most kidney-infiltrating T cells have reduced proliferative capacity, cytokine production, and increased expression of inhibitory receptors, including PD-1⁴⁶. Conversely, recent single-cell transcriptomics data from human lupus nephritis indicate that kidney-infiltrating CD8 T cells express low levels of canonical exhaustion markers, whereas circulating CD8 T cells do show an exhausted phenotype in SLE patients⁴⁷. These contrasting study findings suggest potential discrepancies in human versus murine lupus data. Moreover, the differences in exhausted markers between the circulating and affected organ CD8 T cells in SLE illustrate some of the complexities in understanding the disease pathogenesis.

Double negative T cells

Mature double negative (DN)T cells express the αβ T cell receptor but lack the CD4 and CD8 co-receptors and natural killer (NK) cell markers⁴⁸. Although these cells represent a small proportion of circulating lymphocytes in healthy individuals and are considered quiescent, patients with SLE and mice with lupus-like disease show expansion of the DNT cell population. DNT cells are proinflammatory in SLE and can infiltrate the kidneys, producing significant amounts of IL-17 and IFN-γ⁴⁹. In lupus-prone mice, these cells also increase in parallel with worsening disease⁵⁰.

DNT cells are thought to originate from activated self-reactive CD8 T cells after downregulation of CD8 expression on the cell surface in patients with SLE⁵¹. However, the exact mechanisms and specific factors by which these CD8 T cells escape activation-induced cell death and acquire the DNT cell phenotype are not completely understood. It is possible that self-antigens from apoptotic cells can activate self-reactive CD8 T cells and give rise to DNT cells via downregulation of CD8⁴⁸. This cell population has a pro-inflammatory phenotype, with enhanced tissue migration ability, IL-17 production, and promotion of autoantibody production and renal immune complex deposition^48,49. Improved understanding of the origins, heterogeneity, plasticity and function of DNT cells may reveal potential therapeutic targets in SLE.

γδT cells

γδT cells represent a minor population of circulating lymphocytes. In contrast to conventional αβ T cells, γδT cells do not recognize antigens presented by MHC molecules. Instead, γδT cells directly recognize a large variety of non-peptide molecules such as t-RNA synthetases and glycosides⁵². γδT cells have pleiotropic roles and are potent effectors against pathogens, as these cells can identify specific antigens from biochemical pathways commonly used by bacteria, fungi and parasites⁵³. These cells are also involved in B cell class-switching (in germinal centers or extra-follicular aggregates) and enhancement of plasma cell survival⁵⁴.

Previous studies have reported higher numbers of circulating γδT cells in general in SLE patients as compared to healthy controls⁵⁵. However, on evaluation of γδT cell subsets and when patients are stratified according to timing of SLE onset and disease activity, the differences between SLE patients and controls become more complex. For example, a specific subset of γδT cells with regulatory functions (i.e., CD27⁺CD25^highFoxP3⁺ Vδ1 T cell population) is decreased in the blood of SLE patients. In new-onset patients with SLE a significantly lower proportion of circulating γδT cells was found in comparison with healthy controls. Moreover, absolute γδT cell counts were found to be decreased in patients with active SLE. The counts increased to overall normal levels after SLE treatment. There were also greater counts of the γδ1 subtype in SLE patients compared to healthy individuals⁵⁶. Conversely, in target tissues such as the skin, there is a greater proportion of γδT cells, particularly in those with active disease⁵⁷. Several in vitro and murine lupus models have also demonstrated a potential pathogenic role of γδ T cells in SLE by multiple mechanisms⁵².

T cell Metabolism in SLE

Several studies have demonstrated the impact of metabolic control on T cell differentiation, signaling and pathogenicity. Nutrient availability directly affects the function of immune cells. Abnormalities in oxidative stress, glycolysis, lipid metabolism and mitochondrial dysfunction are thought to contribute to dysregulated T cell responses in SLE, and may explain the aberrant phenotypes in patients and murine lupus models⁵⁸. Specifically, glycolysis-derived oxidative phosphorylation is characteristic of T cells from lupus patients and mice. A predominance of glycolysis and glutaminolysis is also known to promote the generation of Th17 cells, whereas fatty acid and pyruvate oxidation can favor Treg and memory T cell differentiation⁴.

In SLE, T cells are prone to hyperactivation due to TCR rewiring, in which the CD3ζ chain is replaced by FcεRIγ and couples with the spleen tyrosine kinase instead of the ζ-associated protein kinase 70 kDa. This rewiring, mediated by an increase of protein phosphatase 2A activity and high oxidative stress in T cells, leads to increased TCR sensitivity and downstream signaling⁴. Moreover, aberrant lipid raft formation and enhanced co-stimulatory signals from target organs such as the kidney all contribute to increased TCR and co-stimulatory signaling in SLE. Consequently, T cell hyperactivation leads to increased production of reactive oxygen species (ROS) and evidence of oxidative stress in circulating immune cells of patients with SLE⁵⁹.

mTOR, a sensor of cell nutrient status and mitochondrial hyperpolarization, is activated by ROS. mTOR complex 1 (mTORC1) signaling is also increased in SLE. Multiple direct and indirect mechanisms have been implicated in mTORC1 hyperactivation, including oxidative stress, upregulation of the calcium/calmodulin-dependent protein kinase IV (CaMK4), pentose phosphate pathway metabolites, increased expression of the lipid phosphatase PTEN, and genetic factors⁴. This signaling pathway is crucial for CD8 and CD4 T cell differentiation, including Th1, Tfh, and Th17 subsets⁶⁰. In general, mTOR activation also has negative effects on Treg differentiation and function. mTOR blockade by rapamycin inhibits Th17 differentiation while promoting Treg generation and has been shown to reduce SLE disease activity⁶¹. In addition, treatment with the reducing agent N-acetylcysteine, a precursor of glutathione and mTOR inhibitor, reverses the expansion of DNT cells and can lower anti-dsDNA titers in patients with SLE⁶². Other therapeutic agents targeting mitochondrial and cell metabolism, including metformin, have corrected some of the dysfunctional phenotypes in T cells from lupus-prone mice and patients with SLE⁵⁸. Given multiple lines of evidence suggesting metabolic abnormalities directly impact T cell dysfunction in SLE, modulating these pathways in autoreactive T cells represent a promising therapeutic approach in SLE.

Genetics and epigenetics of T cells contributing to SLE

Epigenetic and genome-wide association studies have identified multiple alterations that potentially contribute to T cell dysregulation in SLE⁶³. T cell activation is highly dependent on the major histocompatibility complex (MHC), which is the first loci identified to have a strong genetic association with SLE⁶⁴. CD8+ T cells carrying a STAT4 risk allele, which is associated with a more severe SLE phenotype and an earlier onset of disease, display enhanced IL-12-induced IFN-γ production⁶⁵. In addition, SLE patients carrying the STAT4 risk allele have increased phosphorylation of STAT4 in response to IL-12 and interferon-alpha in CD8+ T cells and are predisposed to have an earlier onset of disease, increased risk of stroke, and severe renal insufficiency^65–67.

Lupus nephritis pathogenesis is attributed to multiple genes affecting T cell signaling, including TNFSF4, which promotes Tfh cell responses via the OX40/OX40L pathway. Expression of TNFSF4 receptors is also associated with nephritis and disease activity in SLE^51,66. The CD47 gene, which regulates T cell production of vascular endothelial growth factor, is downregulated in SLE T cells and is associated with renal disease⁶⁸. Lower expression of SRSF1 in T cells of SLE patients is associated with lymphopenia⁶⁹. Although genetic risk factors contribute to the development of SLE, this does not solely explain the heterogeneity of the disease.

Alteration of epigenetic modifications such as DNA methylation, histone modifications and microRNA, can also contribute to dysregulated T cell phenotypes⁷⁰. DNA methylation results in the silencing of gene expression and is regulated by DNA methyltransferase (DNMT) enzymes and methyl CpG-binding proteins, which function to enlist the help of histone deacetylases and other remodeling factors^3,70,71. Interestingly, mTOR activation and oxidative stress, which are commonly found in T cells from patients with SLE, contribute to hypomethylation in these cells via inhibition of DNMT1³. Hypomethylation of CpG22 in CD4⁺ T cells in patients with SLE is associated with increase in SLEDAI score, whereas hypomethylation of CpG15 is associated with an increase in anti-dsDNA⁷². Similarly, hypomethylation and consequent upregulation of the PRF and GZMB genes has been described in CD8⁺ T cells, which is associated with production of autoantigens and increased disease activity³. DNA methylation also decreases in a dose-dependent manner in CD4⁺ T cells exposed to ultraviolet B in SLE patients⁷³.

Specific SLE disease manifestations have been linked to hypo- and hypermethylation patterns. Renauer et. al, identified specific regions of hypo- and hypermethylation in naive T cells that correspond to cell proliferation and apoptotic pathways in subjects with active or past cutaneous manifestations, including malar and discoid rash⁷⁴. In all SLE patients, irrespective of presence of cutaneous manifestation or renal involvement, hypomethylation was observed in interferon-regulated genes^74,75. Coit et al. identified 64 hypomethylated sites in naïve CD4+ T cells that are unique to lupus nephritis and SLE patients with a history of renal involvement⁷⁵. DNA hypomethylation is also observed in the CD40LG and genes related to arthritis and development of connective tissue in CD4+ T cells, whereas hypermethylation is observed in genes that correspond to metabolic pathways like folate biosynthesis and pentose phosphate pathway⁷⁶.

In addition to DNA methylation, post-transcriptional mRNA modifications can also modulate gene expression. For example, the levels of 5-methylcytosine (m5C), a form of mRNA epigenetic modification, are decreased in CD4⁺ T cells from SLE patients compared to healthy controls. Moreover, lower m5c levels are associated with more severe SLE disease activity⁷⁷.

MicroRNAs (miRNAs) regulate expression of multiple gene targets through repression or degradation of mRNA. Aberrant expression of miRNAs in T cells can affect the downstream expression of target molecules implicated in SLE pathogenesis⁷⁸. Mean expression of six types miRNAs in T cells was found to be lower in SLE patients than in healthy controls, and was positively correlated with serum vitamin D concentration. Interestingly, a vitamin D concentration of <20 ng/ml was identified as a potential risk factor for SLE via dysregulation of miRNA expression⁷⁸.

Histone acetylation has also been implicated in SLE pathogenesis. Reduced histone H3 acetylation and H3K9 methylation is observed in SLE CD4⁺ T cells, and histone marks are observed at the IL-17 and IL-10 gene clusters suggesting increased gene expression. In contrast, histone condensation is seen in the IL-2 clusters⁷⁹. This could relate to the Treg defects observed in SLE patients⁸⁰.

T cell biomarkers and therapeutics in development

As T cells play a central role in promoting B cell differentiation and enhancing production of autoantibodies, efforts focused on targeting T cell pathways in SLE have emerged⁸¹. Unfortunately, many drugs have not progressed in development (Table 1)⁸². Despite some early failures, next generation therapeutics have been developed and are in different phases of clinical trials (Table 2). Dapirolizumab pegol (DZP),a CD40 ligand antagonist, demonstrated improvement in immunological and clinical outcomes in the DZP-receiving group in a phase 2B trial, and a phase 3 trial is currently underway⁸². Over the past decade, the voltage-gated Kv1.3 potassium channels in T lymphocytes have garnered attention as a therapeutic target since these are highly expressed in macrophages and effector memory T cells (Tem) of patients with autoimmune diseases⁸³. Dalazatide, an inhibitor of T_em Kv1.3 channels, decreases the percentage of CD4+ Tem cells expressing HLA-DR^83,84. In an ex-vivo study, dalazatide use led to inhibition of IFN-γ, IL-17, and TNF-α production by CD4+ and CD8+ T cells in SLE; a phase 2 trial is underway⁶⁸. CaMK4 has also emerged as a potential target, given its role in Th17 cell differentiation and IL-17 production⁸⁵.

Table 1.

Clinical trials of biologics targeting T cell pathways that did not progress

T cell Directed Therapeutic	Mechanistic Target	Clinical Trials Identifier	Last Study Phase in SLE Prior to Discontinuation
Ustekinumab	Monoclonal antibody targeting IL- 12 and IL-23	NCT03517722	Phase 3
Abatacept	CTLA-4 agonist that inhibits the CD28 binding to CD80/CD86	NCT01714817	Phase 3
Lulizumab	Anti-CD28 domain antibody	NCT02265744	Phase 2
Theralizumab (TAB08)	Anti-CD28 superagonist	NCT02711813	Phase 2

Table 2.

T cell pathway targeting drugs that are currently being studied or developed for SLE

T cell Directed Therapeutic	Mechanistic Target	NCT Trial No.	Target Patient Population	Most Recent Phase Study completed in SLE	Notable Outcomes
Dalazatide	Kv1.3 channel inhibitor	NCT02446340	Healthy Control & Ex-Vivo Pediatric and Adult SLE	Phase 1b	*Dalazatide inhibited cytokine production by CD4+ and CD8+ Tem *CD8+ T effector memory(Tem) cells expression of Kv1.3 is higher in active lupus nephritis *Kv1.3 may be a useful biomarker for SLE disease activity
Dapirolizumab pegol (DZP)	CD40 ligand antagonist	NCT02804763	Moderate to Severely Active SLE Patients	Phase 2b	*Did not meet the primary endpoint *No differences in treatment adverse reactions between placebo controlled and DZP receiving subjects - drug appears to be well tolerated *Consistent improvement in DZP group in anti-dsDNA antibody levels, and pharmacodynamics markers.
Tacrolimus (TAC) and STA-21 Combination Therapy	Calcineurin inhibitor and TA-21 inhibits STAT3 signaling	N/A	SLE	Preclinical	*TAC suppresses Th1, Th2, and Th17 cells and reduces Treg expression *In combination with STA-21, TAC suppresses GC B Cells, plasma cells and the production of TNF-α
Sirolimus	mTOR pathway inhibition	NCT00779194	Active SLE patients that are unresponsive to conventional medications	Phase 1/2	*Reduction in SLEDAI and BILAG score was observed after 12 months on treatment *CD4+FoxP3+ Tregs expansion in SLE patients when comparing baseline to 6 month data *Sirolimus was safe and efficacious in majority of trial participants

Tacrolimus, a calcineurin inhibitor, blocks IL-2 expression in T cells, and suppress Th1, Th2, and Th17 cytokine production⁸⁶. Additionally, tacrolimus in combination with STA-21, an STAT3 inhibitor, can increase the population of Treg and provide potential beneficial to SLE patients⁸⁶. Sirolimus (rapamycin), an mTOR inhibitor, prevents the development of lupus nephritis in lupus-prone murine models⁸⁷. Results from the phase 1/2 trial determined that the therapeutic was safe and efficacious for patients with active SLE. Use of Sirolimus increased CD4+ memory T cells in SLE patients and resulted in the expansion of CD8+ T cells in those with an increase in mean SLEDAI score⁸⁸. Off-label use of Sirolimus also showed benefit in SLE patients with musculoskeletal involvement, further supporting results from previous studies⁸⁷. Recently, the next generation calcineurin inhibitor voclosporin was FDA approved for the treatment of lupus nephritis⁸⁹. This result was highly encouraging regarding T cell suppressive therapy in SLE and suggests that some of the other T cell-directed therapies in earlier stages of development could be successful.

T cells are also being investigated as prognostic biomarkers to pave the way for precision medicine in SLE. A human immunophenotyping SLE study demonstrated that patients can be stratified into T cell independent, Tfh dominant, and Treg dominant groups. Although these groups could not be differentiated based on clinical differences, Tfh-dominant patients were more resistant to standard SLE therapy^90,91. Additionally, hypomethylation of CHST12 in CD4+ T cells of SLE patients was observed to be 86% sensitive and 64% specific for lupus nephritis, proving to be a potential biomarker⁶⁸.

Summary

T cell dysregulation has been increasingly recognized as central to SLE pathogenesis and is manifested by an imbalance between populations with immunosuppressive functions and pathogenic T cell subsets, which contribute to the break in immune tolerance and ongoing inflammation. Growing recognition of the role of T cells in SLE has led to findings of abnormalities in metabolism, epigenetics and genetic factors contributing to the dysfunctional phenotypes observed in SLE. Greater understanding of T cell dysregulation in SLE is crucial for therapeutic development aimed at correcting the aberrant phenotypes. Identification of biomarkers related to T cell dysfunction as predictors of disease course or treatment response would also be of great benefit for optimal management of patients with SLE.

Synopsis:

T cell dysregulation has been implicated in the loss of tolerance and overactivation of B cells in SLE. Recent studies have identified T cell subsets and genetic, epigenetic, and environmental factors that contribute to pathogenic T cell differentiation, as well as disease pathogenesis and clinical phenotypes in SLE. Many therapeutics targeting T cell pathways are under development, and although many have not progressed in clinical trials, the recent FDA approval of the calcineurin inhibitor voclosporin is encouraging. Further study of T cell subsets and biomarkers of T cell action may pave the way for specific targeting of pathogenic T cell populations in SLE.

Key Points:

• Predominance of pathogenic and dysfunctional T cell subsets over regulatory T cells are central to SLE pathogenesis.

• Abnormalities in metabolic pathways, such as oxidative stress, glycolysis and lipid metabolism, contribute to the dysfunctional T cell phenotypes in SLE.

• T cell epigenetic and genetic alterations are associated with disease activity and clinical phenotypes.

• Although multiple drugs have failed to meet their primary outcomes in SLE, various promising therapeutic agents targeting T cell-related pathways are currently in different phases of development.

Clinical Care Points.

• Various T cell subsets are pathogenic in SLE, promoting systemic autoimmunity and end-organ damage.

• Epigenetic modifications, such as differential DNA and mRNA methylation patterns, could represent novel biomarkers to better characterize and stratify patients with SLE.

• Novel and repurposed therapeutic agents targeting T cell-related pathways could be beneficial to at least a subset of patients with SLE.