Emerging patterns of regulatory T cell function in tuberculosis

A Ahmed; A Vyakarnam

doi:10.1111/cei.13488

. 2020 Sep 6;202(3):273–287. doi: 10.1111/cei.13488

Emerging patterns of regulatory T cell function in tuberculosis

A Ahmed ¹, A Vyakarnam ^1,^2,^✉

PMCID: PMC7670141 PMID: 32639588

A diagrammatic model highlighting T_reg suppression in healthy subjects and subjects with either latent or active pulmonary TB. Individuals infected with TB can either clear the bacteria, become latently infected or develop active TB disease. HLA‐DR⁺CD4⁺ activated T cells are low in healthy and latently infected individuals and T_reg suppression is optimal. However, in active TB, HLA‐DR⁺CD4⁺ T cells expand and T_reg mediated suppression is dampened. Presence of expanded HLA‐DR⁺CD4⁺ T cells compromises PD‐1/PD‐L1 and β‐chemokine‐CCR5 dependent T_reg suppression pathways in TB partly linked to counter‐regulation by elevated expression of IL‐17A, IFNγ, IL‐22 by the expanded HLA‐DR⁺CD4⁺ T cell subset.

graphic file with name CEI-202-273-g004.jpg

Keywords: HLA‐DR, T_eff, T_reg, tuberculosis

Summary

Tuberculosis (TB) is one of the top 10 causes of mortality worldwide from a single infectious agent and has significant implications for global health. A major hurdle in the development of effective TB vaccines and therapies is the absence of defined immune‐correlates of protection. In this context, the role of regulatory T cells (T_reg), which are essential for maintaining immune homeostasis, is even less understood. This review aims to address this knowledge gap by providing an overview of the emerging patterns of T_reg function in TB. Increasing evidence from studies, both in animal models of infection and TB patients, points to the fact the role of T_regs in TB is dependent on disease stage. While T_regs might expand and delay the appearance of protective responses in the early stages of infection, their role in the chronic phase perhaps is to counter‐regulate excessive inflammation. New data highlight that this important homeostatic role of T_regs in the chronic phase of TB may be compromised by the expansion of activated human leucocyte antigen D‐related (HLA‐DR)⁺CD4⁺ suppression‐resistant effector T cells. This review provides a comprehensive and critical analysis of the key features of T_reg cells in TB; highlights the importance of a balanced immune response as being important in TB and discusses the importance of probing not just T_reg frequency but also qualitative aspects of T_reg function as part of a comprehensive search for novel TB treatments.

Regulatory T (T_reg) cells: a brief introduction

Extensive experimental evidence shows that it is not only important to mount an effective immune response, but equally crucial to efficiently control it. A vital cog in the immune regulation machinery is a class of CD4⁺ T cells, termed regulatory T (T_reg) cells. T_reg cells have been extensively studied, particularly in autoimmune disorders, as potential therapeutic targets. T_regs can be broadly classified as (a) thymic or tT_regs/natural or nT_regs, which originate in the thymus, and (b) induced or iT_regs/peripheral or pT_regs, which develop in the periphery during T cell activation. Development of nT_regs is influenced by signal strength [1, 2] co‐stimulatory CD28 signalling, inducible T cell co‐stimulator (ICOS)/ICOS ligand (ICOS/ICOSL) interactions and thymic stromal lymphoprotein (TSLP) [3, 4, 5]. Transcription factor forkhead box protein 3 (FoxP3) is a key regulator of T_reg development, maintenance and suppressive function [6, 7, 8, 9, 10] and its expression in CD4⁺CD25^highFoxP3⁺ tT_regs is positively regulated by IL‐2 [11], transcription factors nuclear factor of activated T cells (NFAT), signal transducer and activator of transcription 5 (STAT‐5) and ‘small’ and ‘mothers against decapentaplegic’ homologue 3 (SMAD3) [12, 13, 14] and negatively regulated by phosphatidyl inositol‐3 kinase (PI3K), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) [15]. However, FoxP3 expression can also be induced upon exposure to non‐self antigens in CD4⁺FoxP3^– conventional T cells, which then differentiate into FoxP3⁺ T_regs known as pT_regs/iT_regs by a process regulated by cytokines transforming growth factor (TGF)‐β and interleukin (IL)‐2 [16, 17], suboptimal CD28‐mediated co‐stimulation [18] and suboptimal T cell receptor (TCR) triggering [19, 20]. While nT_regs maintain tolerance and homeostasis systemically, pT_regs/iT_regs are crucial for dampening over‐exuberant antigen‐specific immune responses locally [21]. Inducible T regulatory type 1 (Tr1) cells, a subclass of pT_regs/iT_regs, mediate suppressive effects via the immune‐regulatory cytokine IL‐10 [22]; cell surface markers CD49b and lymphocyte‐activation gene 3 (LAG3) promote Tr1 differentiation [23]; and IL‐27, IL‐6, IL‐21, IL‐10, immature dendritic cells (DCs) and plasmacytoid DCs promote Tr1 expansion [24, 25, 26, 27, 28]. Other iT_reg subsets include T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine‐based inhibition motif (ITIM) domain or TIGIT‐1⁺ cells, which express high levels of T_reg signature genes [e.g. IL‐10, cytotoxic T lymphocyte antigen 4 (CTLA‐4), LAG3, FoxP3, etc.] capable of suppressing Th1 and Th17 responses via a mechanism involving expression of fibrinogen‐like protein 2 (Fgl2) post‐ligation of TIGIT with CD155 [29]; IL‐35‐producing suppressive T (Tr35) cells that suppress via secretion of regulatory cytokine IL‐35 [30]; and IL‐10‐producing non‐pathogenic Th17 cells that are capable of controlling autoimmune inflammation, e.g. rheumatoid arthritis, inflammatory bowel disease, etc. [31].

T_reg suppression mechanisms can be contact‐dependent or ‐independent (Fig. 1). A breakdown in T_reg suppression can occur due to (i) reduction in T_reg frequencies, (ii) loss of T_reg immunosuppressive capacity or due to (iii) resistance acquired by effector T cells (T_eff) to T_reg‐mediated suppression, with impact on a variety of clinical conditions (Tables 1 and 2) in addition to TB (Table 3). This review focuses on how these mechanisms may contribute to disease in the context of TB.

Table 1.

A summary of clinical conditions both autoimmune (peach highlighted) and infection (blue highlighted) where T_reg frequency and function are compromised.

Sl. No.	Clinical Condition	Finding	Reference
1.	Rheumatoid arthritis (RA)	Polymorphisms in FoxP3 gene associated with reduced frequency of T_reg, TGF‐β and IL‐10 in RA.	[32]
		Increased circulating HLA‐DR⁺T_regs or inflammation‐associated T_regs which are suppressive but have similar TCR repertoire as pathogenic CD4⁺ T cells.	[33]
		Reduced frequencies of nT_reg in patients with RA.	[34]
		T_regs unable to suppress spontaneous generation of TNF‐α in synovial cells of RA patients due to reduced expression of CTLA‐4 and LFA‐1.	[35]
2.	Multiple Sclerosis (MS)	CD4⁺CD25⁺ T_reg cells/T_reg‐derived exosomes from MS patients are inefficiently suppressive. Circulating exosomes with significantly high miRNA let‐7i in MS patients, inhibit T_reg function through an IGFR1 and TGFBR1 mechanism.	[36, 37, 38]
2.	Multiple Sclerosis (MS)	CD25⁺CD127^low T_reg development and function are perturbed. CD39⁺FoxP3⁺ memory T_reg are diminished in MS patients. Expression of PD‐1 is high in these T_regs in MS, suggesting possible exhaustion and compromised function.	[39, 40]
3.	Systemic Lupus Erythromatosis (SLE)	CD25⁺Lag3⁺ T cells, expressing FoxP3 and IL‐17A, but not being suppressive are increased in patients with SLE. The frequency of CD25⁺Lag3⁺ cells positively correlates with SLE disease activity.	[41]
4.	Type 1 Diabetes	Reduced suppressive function of T_reg cells in type 1 diabetes patients possibly due to reduced CD39 expression on memory T_reg cells.	[42]
		Differentiation and stability of Tregs is impaired in Type 1 diabetes through a miRNA‐1423p‐dependent mechanism.	[43]
		FoxP3 expression declines with type 1 diabetes disease progression, suggesting loss in T_reg function. The rate of loss is greatest in Peptidase inhibitor (Pi)‐16 or Pi16⁺ T_reg cells.	[44]
5.	Malaria	FoxP3⁺T_reg cells increase in humans and mice during blood stage malaria and hamper Th and Tfh–B cell interactions.	[45]
5.	Malaria	Frequency of FoxP3⁺ T_regs declines in children with age in high exposure malaria settings.	[46]
6.	Dengue	T_reg frequencies are higher in mild cases of dengue compared to moderate cases and healthy controls.	[47]
6.	Dengue	T_reg frequencies in acute dengue fever are high and most of the expanded T_reg population is comprised of naive T_regs with poor suppressive potential.	[48]
7.	HIV	HIV‐infected paediatric slow progressors have higher T_reg absolute numbers with a suppressive phenotype compared to rapid progressors.	[49]
		CD4⁺CD25^highCD62L^high T_regs are depleted in HIV infection and this correlates with immune activation.	[50]
		HIV⁺ elite suppressors maintain higher levels of T_reg and lower immune activation compared to progressors.	[51]
		Frequency of PD‐1⁺ T_regs increases in HIV and blockade of the PD‐1/PD‐L1 pathway increases TGF‐β and IL‐10 in CD4⁺CD25^highCD127^lowT_reg cells.	[52]
		Individuals who do not respond to ART have fewer and dysfunctional T_regs with defects in mitochondrial function compared to healthy controls and HIV patients who respond to ART.	[53]
8.	Candida infection	Candida albicans infection in a mouse model drives expansion of T_regs which corresponds with increased fungal burden. Expanded T_regs suppress Th1 and Th2 but promote pathogenic Th17 responses	[54, 55]
9.	Leishmaniasis	Foxp3⁺IL‐10⁺ T_reg cells are enriched in bone marrow of visceral leishmaniasis patients with high parasite load compared to those with low parasite load.	[56, 57]
9.	Leishmaniasis	Frequency of CD4⁺CD25^highFoxP3⁺ T_reg cells correlates with parasite load in Kala‐azar patients infected with Leishmania donovani.	[56, 57]

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T_reg= regulatory T cell; ART = antiretroviral therapy; FoxP3 = forkhead box protein 3; TGF = transforming growth factor; IL‐10 = interleukin 1; HLA‐DR = human leucocyte antigen D‐related; CTLA‐4 = cytotoxic T lymphocyte antigen 4; LFA‐1 = lymphocyte function‐associated antigen 1; IGFR1 =insulin like growth factor 1 receptor; LAG3 =lymphocyte activation gene 3; Th = T helper; Tfh = T follicular helper cell; PD‐1 = programmed cell death protein 1; PD‐L1 = programmed cell death ligand 1.

Table 2.

A summary of clinical conditions where T_eff susceptibility to T_reg‐mediated suppression is altered.

Sl. no.	Clinical condition	Finding	Reference
1.	Type I diabetes	Resistance of T_eff cells to T_reg‐mediated suppression via faster activation of STAT‐3 signalling post‐TCR stimulation in type 1 diabetes patients.	[58]
1.	Type I diabetes	Teffs from type 1 diabetes patients are resistant to suppression mediated by CD4⁺CD25⁺ T_reg cells.	[59, 60]
2.	Rheumatoid arthritis (RA)	Synovial CD161⁺Th17 cells are resistant to T_reg‐mediated suppression in RA patients.	[61]
3.	HIV infection	Increased sensitivity of CD4⁺CD25⁻ T_eff cells to T_reg‐mediated suppression in HIV⁺ asymptomatic individuals compared to progressors.	[62, 63]
		HLA‐B27 and HLA‐B57 restricted CD8⁺ T cells associated with protection against HIV are not suppressed by T_reg cells.
4.	Tuberculosis	HLA‐DR⁺CD4⁺ memory T cells which are IFN‐γ^highIL‐2^highIL‐17^highIL‐22^high are resistant to T_reg ‐mediated suppression in TB patients.	[64]

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T_reg= regulatory T cell; T_eff = effector T cells; TB = tuberculosis; IFN = interferon; IL = interleukin; HLA‐DR = human leucocyte antigen D‐related; STAT‐3 = signal transducer and activator of transcription‐3; TCR = T cell receptor.

Table 3.

A summary of findings on T_reg frequency and function from animal models of infection and TB patients

	Study model	Findings		Refs
	Study model	T_reg frequency	T_reg function	Refs
Mice	Mice infected with Mtb H37Rv via aerosol.	ESAT‐6‐specific FoxP3⁺ STAT‐3 expand at day 21 and contract by days 32–35 post‐infection via an IL‐12 driven mechanism	Expanded ESAT‐6‐specific T_reg cells express CD25, CTLA‐4, GITR, CD103, ICOS, suggesting that they are activated and immune‐suppressive.	[65]
		CD4⁺FoxP3⁺/Mtb‐specific FoxP3⁺ T_reg cells expand in pulmonary lymph node and lungs by day 21 post‐infection.	Depletion of FoxP3⁺ T_regs reduces CFU in lungs and spleen at day 23. Adoptive transfer of T_reg cells delays accumulation of Mtb‐specific T_eff cells at day 21, implying that early T_reg expansion is detrimental.	[66, 67]
		CD4⁺FoxP3⁺ T_reg cells expand in lungs and pulmonary lymph node of Mtb‐infected mice starting from days 10 to 60 post‐infection	Adoptive transfer of CD4⁺FoxP3⁺ T_reg cells along with T_eff cells into Rag^−/− increase CFU burden by ~1 log in spleen and lungs compared to mice that receive only T_eff cells, implying that presence of T_reg can contribute to disease.	[68]
	Intranasal infection with M. bovis BCG Pasteur	Expansion of CD25⁺FoxP3⁺ T_reg cells in the lungs by days 21–25 post‐infection.	Depletion of T_reg increases frequency of mycobacteria‐specific IL‐2⁺/IFN‐γ⁺ cells but does not affect bacterial burden.	[69]
	Mtb H37Rv, Mtb Kurono, Mtb Erdman and Mycobacterium bovis BCG Tokyo aerosol‐infected mice	T_reg frequencies were not determined	Depletion of T_reg reduces CFU burden at 21 days but not at 35 days post‐infection, implying early T_reg expansion is detrimental. Also, CD4⁺CD25⁺ T_reg cells from chronically BCG or Mtb‐infected mice fail to suppress PPD‐induced proliferation and IFN‐γ expression.	[70]
	Mtb H37Rv intravenous infection in TB‐sensitive C3HeB/FeJ and TB‐resistant C3H/HeN	CD25⁺FoxP3⁺ T_reg frequencies are higher in C3H/HeN compared to C3HeB/FeJ mice. Administration of heat‐killed environmental mycobacteria M. maserensis boosts T_reg frequencies in C3HeB/FeJ mice.	Boosting T_reg frequencies by heat‐killed M. maserensis decreases TB‐induced lung pathology and improves survival in C3HeB/FeJ mice.	[71]
	Mtb H37Rv aerosol infection in TB‐resistant C57BL/6JCit and TB‐sensitive I/St mice	CD25⁺FoxP3⁺ T_reg frequencies are higher in B6 mice compared to I/St mice	B6 have fewer activated CD25⁺FoxP3⁻ Th cells and reduced pathology compared to TB‐sensitive I/St mice.	[72]
Non‐human primate	Cynomolgous macaques infected with Mtb Erdman by bronchoscopic instillation.	CD4⁺FoxP3⁺ T_reg and total CD4⁺ cells are higher in Mtb‐ positive compared to ‐negative lung and lymph node tissue autopsied from infected animals. Macaques with latent TB have higher peripheral T_reg frequencies at baseline and 8 weeks post‐infection compared to animals with active TB. Peripheral T_reg frequencies increase in active TB macaques from weeks 10 to 28 post‐infection.	PHA and culture filtrate protein (CFP)‐induced proliferation of PBMC was lower at baseline and 6 weeks post‐infection in latent TB compared to active TB macaques, suggesting higher T_reg frequencies in the former and also that higher T_reg frequencies is a predisposing factor to acquisition of latent rather than active TB.	[73]
Non‐human primate		IL‐2 administration in early infection expands CD4⁺CD25⁺FoxP3⁺, CD8⁺CD25⁺FoxP3⁺ T_reg and CD4⁺ and CD8⁺ effector cells.	Administration of IL‐2 reduced TB‐induced inflammation and lesions, suggesting that IL‐2 expanded effector as well T_reg cells contribute to anti‐TB immunity.	[74]
Human	PBMC from healthy latent TB negative and active TB subjects. Cells from sites of TB infection (pleural, ascitic and pericardial fluids) analyzed	Increased frequencies of CD4⁺CD25⁺ T_regs in peripheral blood compared to healthy controls. Also, in TB T_reg are higher at sites of infection compared to peripheral blood.	Depletion of CD4⁺CD25⁺ cells from PBMC cultures from TB subjects results in higher Mtb‐specific IFN‐γ production implying presence of functional T_regs.	[75]
		Increased frequency of CD4⁺CD25⁺FoxP3⁺ T_reg cells in peripheral blood and pleural fluid of TB patients compared to healthy donors.		[76]
		Frequencies of peripheral CD4⁺CD25^+/highCTLA‐4⁺ and CD4⁺CD25^+/highFoxP3⁺ are higher in TB compared to healthy controls.	CD4⁺CD25^+/high T_reg cells can suppress BCG‐induced IFN‐γ production in in‐vitro cultures of PBMC from TB patients, implying presence of functional T_regs.	[77]
	Sputum culture‐positive and ‐negative MDR‐TB subjects	Mtb‐specific CD69⁻CD127⁻CD25^highFoxP3⁺Ki67⁺HLA‐DR⁻ T_reg frequencies are higher in sputum culture‐positive (higher bacterial burden) than ‐negative patients.	T_reg function not studied	[78]
	PBMC from pulmonary TB and tuberculin⁺ subjects analyzed	No significant difference in frequencies of peripheral PPD‐specific CD4⁺CD25⁺FoxP3⁺ T_reg cells in TB patients and controls.		[79]
	PBMC from latent (quantiferon positive) TB; pulmonary TB; pulmonary TB after treatment and healthy quantiferon‐negative adults analyzed	Higher peripheral CD4⁺CD25^+/high cells in TB patients. No significant difference in frequencies of peripheral CD4⁺CD25⁺CD127^lowFoxP3⁺ T_reg between clinical categories studied.		[80]
		No significant difference in frequencies of peripheral CD4⁺CD45RA⁻CD25⁺, CD4⁺CD25⁺CD45RA⁻CD127^low and CD4⁺CD25⁺CD45RA⁻CD127^lowFoxP3⁺ T_reg cells.	Suppression of proliferation of CD4⁺ effector T cells by CD45RA⁻CD4⁺CD25⁺ and CD45RA⁻CD4⁺CD25⁺CD127^low T_regs is dampened in active TB.	[64]

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T_reg= regulatory T cell; STAT‐3 = signal transducer and activator of transcription‐3; Mtb = Mycobacterium tuberculosis; ESAT‐6 = early secretory antigenic target‐6; FoxP3 = forkhead box protein 3; IL = interleukin; PBMC = peripheral blood mononuclear cells ; CTLA‐4 = cytotoxic T lymphocyte antigen 4; PPD = purified protein derivative; PHA = phytohaemagglutinin; CFU = colony‐forming units; BCG = Bacille Calmette–Guérin; MDR‐TB = multi‐drug‐resistant tuberculosis.

Tuberculosis

Mycobacterium tuberculosis (Mtb), the causative agent of TB, can either cause latent or active TB disease, with the majority of people developing asymptomatic infection, commonly referred to as latent TB. However, increasing evidence shows that the asymptomatic state of TB is not necessarily a condition where TB bacilli are dormant, and therefore the term ‘latent TB’ may be misleading. Indeed, radiography and positron emission tomography/computed tomography (PET/CT) scans of subjects with asymptomatic Mtb infection highlight a condition that is highly heterogeneous, where some subjects have lung lesions from which viable, metabolically active bacteria can be isolated [81], while others lack detectable lung lesions. Irrespective of this heterogeneity, only 5–10% of subjects with latent asymptomatic TB are known to progress to active TB disease during their lifetime, with the mechanisms driving such progression being an area of active research that, in turn, is limited by the lack of definitive correlates of protection, which is beyond the scope of this review. Progression from latent to active TB can be due to several reasons, among which HIV co‐infection is a major predisposing factor [82]. Although Mtb is spread through aerosols and replicates in lung epithelial cells, it can also replicate in lymph nodes, bones, stomach, kidneys and other organs causing extrapulmonary TB. In extreme cases Mtb can be systemically disseminated, precipitating a potentially fatal condition known as miliary TB. Upon entering the host through aerosol, Mtb bacilli are taken up by alveolar macrophages by phagocytosis facilitated by cell surface receptors, e.g. Toll‐like receptors (TLR), C‐type lectin receptors (CLR), scavenger receptors (SR), complement receptors (CR) and Fc receptors (reviewed in [83]) and replicate in macrophages in the lung parenchyma. Primed DCs traffic to the lymph node and trigger activation of adaptive immune cells which are recruited to the lung, and gradually an organized structure, the granuloma, begins to form, which comprises a core with replicating bacilli, surrounded by an inner ring of epithelioid interlocked macrophages, neutrophils and foam cells and an outer ring of T, B and NK cells [84]. With time, necrosis takes place and accumulation of necrotic material leads to formation of a caseum and the granuloma is known as a ‘caseating granuloma’, which can also undergo cavitation leading to Mtb dissemination [84, 85]. The resolution of infection within the granuloma relies upon host immune responses, which can potentially be impacted by T_reg cell function. Indeed, the role of T_regs has been studied in the context of the early acute stage of Mtb infection and the chronic phase of infection with evidence from mouse, primate and human studies, as summarized below.

T_regs in TB

Acute phase of infection: an analysis of animal model studies suggests early expansion to be detrimental

Mouse models highlight the impact of T_regs on TB to be phase‐specific with T_reg frequencies inadvertently high in the acute phase, which is detrimental for infection control [65, 66, 67, 68, 69, 70]. Aerosol infection of mice with mycobacteria leads to activation of CD4⁺ T_eff cells by infected DCs in the pulmonary lymph node at approximately day 11 and subsequent expansion and accumulation of CD4⁺ (effector and regulatory) T cells in the lungs by days 14–21 [65]. Significant disease‐associated lung pathology and colony‐forming units (CFU) burden can be observed at days 14–21, and this period can be classified as the early phase of infection in mice [65, 69, 70]. Time‐points subsequent to this, e.g. 4–7 weeks post‐infection, can be classified as late stages of infection [65, 69, 70]. While time‐lines for early and late phases can vary with multiplicity of infection, in general 50–200 Mtb CFU results in increased T_reg frequencies in lung and pulmonary lymph node at 10–21 days, which is maintained until 60–127 days post‐infection [67, 68]. This early expansion was found to be deleterious to emerging protective anti‐TB Th responses [66, 67, 68, 69]. Depletion of T_regs in C57BL/6 mice by systemic administration of anti‐CD25 three days prior to infection with Bacille Calmette–Guérin (BCG) resulted in enhanced culture filtrate protein (CFP)‐specific IFN‐γ⁺ and IL‐2⁺ CD4⁺ cells in lungs and spleen of BCG‐infected mice 14 days post‐infection, suggesting that the presence of T_reg cells hinders the appearance of protective Th1 responses [69]. Also, adoptive transfer of CD25⁺ T_reg into Mtb‐infected mice leads to reduced frequencies of Mtb‐specific T_eff cells in the lungs at 14–17 days post‐aerosol infection [66]. Importantly, the absence of protective Th1 responses due to expansion of T_regs leads to increased bacterial burden in the acute phase [67]. However, this dampening effect of T_regs on protective immune responses is transient and not evident in later stages of infection [65, 69, 70]. Depletion of CD25⁺ T_regs had no effect on CFU burden or lung pathology in BCG or Mtb Erdman‐infected mice at days 21 and 44 post‐infection [69]. Similar results were reported in another study, where T_reg depletion in Mtb Erdman‐ or Kurono‐infected DBA/2 mice reduced CFU at 2 weeks post‐infection, but had no effect on bacterial burden or pathology subsequently at 3 and 5 weeks [70]. It is important to note that depletion of T_regusing anti‐CD25 as described above [69, 70] has the disadvantage of also depleting activated CD25⁺ T_eff cells. Nevertheless, studies carried out in mice using approaches of T_reg depletion [67, 69, 70] and adoptive transfer [66, 68] have demonstrated that T_reg cells expand in the early phase of Mtb infection. However, it has also been now demonstrated in mice that Mtb‐specific T_regs which expand early during infection are culled via IL‐12 driven expression of T‐bet by 32 days post‐infection, T‐bet being known for its pro‐apoptotic effects [65]. How Mtb infection drives this early expansion of Mtb‐specific T_regs, which is beneficial to the pathogen, remains to be elucidated.

Chronic phase: animal model studies show loss in T_reg frequency or failure to recruit T_regs to site of infection can be detrimental

In contrast to the role of T_regs in dampening protective Th responses in the early/acute stage of infection in murine models, several studies in mouse and primate models highlight that T_regs might be potentially beneficial by regulating excessive inflammation in the chronic phase of infection. Comparison of TB disease progression and pathology in TB resistant and TB‐susceptible mouse strains showed TB‐resistant mouse strains to have higher T_reg frequencies and consequently less TB‐induced lung pathology in the chronic phase of the disease [71, 72] compared to TB‐sensitive mice, which recruit significantly fewer T_regs to the lung [72]. Interestingly, oral administration of heat‐killed M. maserensis (environmental mycobacterium) in TB‐sensitive C3HeN/FeJ mice resulted in a boost in T_reg frequencies with a reduction in lung pathology and improved survival [71]. These observations have been corroborated in non‐human primate models of TB infection, where cynomolgus macaques infected with 25 CFU of Mtb Erdman can either develop active TB or establish latency [73]. In this experimental system it was observed that macaques that developed latent TB had higher basal pre‐infection T_reg frequencies compared to animals that develop active disease [73]. In a separate study, IL‐2 administered either pre‐ or post‐Mtb infection in macaques resulted in T_reg expansion which, in turn, led to reduced bacterial burden and TB‐induced pathology, suggesting that expansion of T_reg cells in the later stage of chronic TB infection can help to control excessive TB‐induced inflammation [74].

Human studies

In contrast to animal model studies, where changes in circulating T_reg frequency can impact infection levels, reports of T_reg frequencies in human TB are varied. Some studies show an increase in peripheral T_reg frequencies in TB [75, 76, 77, 78]. However, our study [64] and others [79, 80] found no differences in peripheral T_reg frequencies between pulmonary TB patients and healthy controls. This disparity may be linked to differences in markers used for T_reg delineation, which vary and can include CD4 and CD25 [75]; CD4, CD25 and FoxP3 [76, 79], a combination of CD4, CD45RA/CD45RO, CD127, CD25 and FoxP3 to identify memory T_regs [64, 80] or CD4⁺CD127^lowCD25⁺FoxP3⁺CD45RO⁺Ki67⁺ to identify activated T_reg cells [80]. Beyond variation in markers used for definition, a further limitation of only tracking T_reg frequency to define T_reg function in a disease such as TB is the impact of trafficking; thus, T_reg frequencies have been shown to be higher at the site of infection in the broncheoalveolar lavage compared to that in the peripheral blood of pulmonary TB subjects [75, 86].

Chronic phase: novel qualitative studies of T_reg function in humans highlight emergence of T_reg‐resistant T effectors in chronic TB

Many studies have probed T_reg frequency; however, few human or animal model studies have analyzed qualitative aspects of T_reg function in TB. Some studies have shown that T_reg cells from pulmonary TB patients retain their capacity to suppress autologous T_eff cells [87, 88, 89]. Data from our laboratory show that autologous suppression mediated by CD4⁺CD45RA⁻CD25⁺CD127^low memory T_reg cells isolated from subjects with pulmonary TB in south India is significantly compromised [64]. By testing isolated T_regs from healthy controls on T_eff isolated from TB subjects and vice versa, we demonstrated that this impairment is not due to the loss of suppressive potential of T_reg cells isolated from TB subjects; instead, it is due to the effector cells from TB subjects acquiring resistance to T_reg‐mediated suppression [64]. Thus, CD127^lowCD25⁺ T_reg cells from TB subjects were effective in suppressing T_eff from healthy controls but not those from TB subjects; conversely, T_reg isolated from healthy controls effectively suppressed autologous T_eff but failed to suppress T_eff from TB subjects [64]. Phenotypical analysis of the T_reg‐resistant T_eff isolated from TB subjects highlighted the presence of a significant proportion of highly activated cells that expressed HLA‐DR and CD38; depletion of the HLA‐DR⁺ subset, in particular, restored sensitivity of HLA‐DR⁻ T_eff to autologous T_reg suppression, thereby confirming that resistance of T_eff from TB subjects to T_reg‐mediated suppression was due to the presence of HLA‐DR⁺ cells [64]. The expansion of HLA‐DR⁺CD4⁺ T cells in TB is driven by infection, as anti‐tubercular (anti‐TB) treatment reduced the frequencies of HLA‐DR⁺CD4⁺ T cells [64, 90, 91]; indeed, we have shown that by dampening the frequency of HLA‐DR⁺ cells, anti‐TB treatment restores T_eff cell sensitivity to autologous T_reg cell‐mediated suppression [64]. Consequently, measuring HLA‐DR⁺CD4⁺ T cell frequency can potentially be used to monitor treatment responses and predict efficacy of treatment [91]. In this context, our observation that HLA‐DR⁺CD4⁺ T_eff cells resistant to T_reg‐mediated suppression provides a mechanistic basis for how the expansion of HLA‐DR⁺ T effectors may be detrimental in TB [64]. The findings from our study are summarized in Fig. 2.

Fig. 2 — A diagrammatic model which highlights the difference in T_reg suppression in healthy, latently infected individuals and active TB subjects in context of expansion of HLA‐DR⁺CD4⁺ memory T cells. Individuals infected with TB can either clear the bacteria, become latently infected or develop active TB disease. There is also a possibility of reactivation of TB in latently infected subjects. The reasons for this can be HIV co‐infection, treatment with check‐point inhibitors such as anti‐PD‐1, therapies such as anti‐TNF for rheumatoid arthritis, etc. HLA‐DR⁺ activated cells are low in healthy and latently infected individuals and T_reg suppression is good. However, in active TB, HLA‐DR⁺CD4⁺ T cells expand and T_reg‐mediated suppression becomes poor. The T_reg suppression pathways that are rendered inactive in TB are the PD‐1/PD‐L1 and β‐chemokine‐CCR5‐dependent. The reason for their becoming inactive could be possible counter‐regulation by IL‐2, IL‐17A, IFN‐γ and IL‐22 that are secreted by the expanded HLA‐DR⁺CD4⁺ T cells.

This observation of the emergence of T_reg‐resistant T_eff in TB is consistent with data from other chronic inflammatory conditions, particularly autoimmune disorders (Table 2). CD161⁺Th17 cells enriched in the synovial fluid of rheumatoid arthritis patients are resistant to T_reg‐mediated suppression and their depletion restores suppression in in‐vitro cultures [61]. A similar phenomenon of the emergence of suppression resistant effectors has been reported in systemic lupus erythromatosis [92], multiple sclerosis [93], type 1 diabetes [59, 94] and juvenile idiopathic arthritis [95], with potentially varying mechanisms underpinning such resistance. In multiple sclerosis, it was attributed to high T_eff cell‐derived granzyme B [93]; in type 1 diabetes due to down‐regulation of TGF‐βRII on T_eff cells and consequently reduced TGF‐β‐mediated suppression [94] and in juvenile idiopathic arthritis, as in TB [64], due to expansion of activated CD69⁺HLA‐DR⁺ T_eff cells which were T_reg suppression‐resistant [95].

Mechanisms that underpin T_reg dysregulation in TB

Evidence for altered expression of cell surface molecules on T_eff that are important for engaging with T_reg cells

T_reg cells suppress via a variety of contact dependent and independent mechanisms (Fig. 1). Some of the key molecules shown to be involved in promoting T_reg suppression include CTLA‐4, PD‐1, CD39, CD73, PD‐L1, LAG3, etc. Several lines of data show some of these molecules, e.g. PD‐1, PD‐L1, CD39, CD73 and LAG3, are altered in TB. PD‐1 and PD‐L1 expression is elevated in CD4⁺ T cells from TB subjects compared to healthy controls [96]; CD39 and CD73 are increased in lung parenchymal CD4⁺ T cells of Mtb‐infected mice [97] and LAG3 is increased in granuloma of macaques with active TB compared to those with latent TB [98]. However, the function of these molecules has not been specifically studied in the context of T_reg suppression in TB. Our study of transcriptomic and functional analysis of cells from pulmonary TB patients provides evidence for a role for PD‐1/PD‐L1 and β chemokine/C‐C chemokine receptor type 5 (CCR5) interactions [64]. We identified that in TB the expanded subset of HLA‐DR⁺ T_eff cells is resistant to T_reg‐mediated suppression while HLA‐DR⁻ T_eff cells remain sensitive; a cellular population comprising both these subsets (HLA‐DR⁺ and HLA‐DR⁻) was rendered resistant to T_reg‐mediated suppression, indicating the function of HLA‐DR⁺ effectors to be dominant in this mixture [64]. To probe the underlying mechanisms, we captured HLA‐DR⁻ and total (HLA‐DR⁺ and HLA‐DR⁻) cell fractions from subjects with confirmed treatment‐naive pulmonary TB [diagnosed by presence of acid‐fast bacilli (AFB) in sputum and Genexpert positivity (Fig. 3a)] and analysed the transcriptome of these cells through RNA sequence analysis over time post‐activation with anti‐CD3/anti‐CD28 (Fig. 3b). Gene expression analysis of each cell fraction post‐activation relative to the unstimulated control allowed identification of longitudinal changes, while comparison of the two fractions highlighted differentially expressed genes [64]. Of the 193 and 89 differentially expressed genes identified in the HLA‐DR⁻ and total T_eff fractions, respectively, at 2 h post activation, elevated expression of PD‐L1 and β‐chemokines were noted to be significantly elevated in HLA‐DR⁻ T_reg‐sensitive T_eff (Fig. 3c). Through blocking studies, we confirmed the functional significance of both pathways in T_reg‐mediated suppression of HLA‐DR⁻ T effectors, pointing to the importance of these pathways in maintaining T_reg‐mediated homeostasis in TB [64]. Our findings are summarized in Fig. 2. PD‐1/PD‐L1 interactions and β‐chemokine/CCR5 interactions have been previously implicated in promoting T_reg‐mediated suppression [99, 100]. C‐C motif chemokine ligand (CCL)3 and CCL4 secreted by T_regs serve as chemoattractants for T_eff cells, and T_eff cells from mice deficient in CCL3 and CCL4 fail to migrate and conjugate with T_reg cells [100]. Moreover, T_regs from type 1 diabetes patients are deficient in CCL3 and CCL4, and this compromises their ability to suppress [100].

Fig. 3 — T_reg suppression resistant total T_eff and T_reg suppression sensitive HLA‐DR⁻ T_eff cells have distinct expression patterns with respect to certain cytokines and cell surface receptors. (a) A brief summary of clinical details of treatment naive pulmonary tuberculosis (TB) donors, including sputum acid fast bacilli (AFB) and Genexpert test results. (b) An outline of methodology used for sorting and archiving of total and HLA‐DR⁺‐depleted (HLA‐DR^‐) T_eff cell populations for RNA‐Seq analysis, as described previously [64]. Briefly, total T_eff (comprising HLA‐DR⁺ and HLA‐DR⁻ cells) and HLA‐DR⁻ Teff were sorted by flow cytometry from 5 pulmonary TB patients. RNA was isolated from both cell fractions at 0, 2, 24 and 96 h post‐activation with anti‐CD3/CD28 mitogenic beads and subjected to sequencing using the Illumina NEXTSeq 500 platform (see [64]). Activation‐induced longitudinal changes in gene expression was first determined relative to the unstimulated control using a cut‐off of P < 0·05, log₂ fold change (FC). Next, genes differentially expressed with time were compared between the total (T_reg ‐resistant) *versus* HLA‐DR⁻ (T_reg‐sensitive) T_eff cells. (c) The database of essential genes (DEG) list was mined for genes implicated in T cell function. A summary of these results is shown. The numbers in boxes denote log₂ FC for expression at 2, 24 and 96 h compared to unactivated cells at baseline for each cell fraction. For further details on procedure and complete DEG list please see reference 64.

Apart from differences in PD‐L1 and β‐chemokine levels (Fig. 2), our transcriptome analysis of T_reg‐sensitive HLA‐DR⁻ and suppression‐resistant HLA‐DR⁺ cells identified several additional cell surface markers [CD46, TNF‐related apoptosis inducing ligand (TRAIL), TNF receptor‐associated factor (TRAF)1, TRAF3, FAS ligand (FASLG), CD30 and semaphorin 7A (SEMA7A)] (Fig. 3c), some of which have previously been implicated in T_reg function [101, 102, 103, 104]. Engagement of complement receptor CD46 results in suppression of bystander CD4⁺ T cells via an IL‐10‐dependent mechanism [101, 102]. CD46 cross‐linking also suppresses mycobacteria‐specific CD4⁺ T cell responses [105]. TRAIL is a regulator of T cell activation; its absence leads to autoimmunity and reduction in T_reg frequencies, while its presence dampens Th1 responses and boosts T_regs [103]. TRAF1 inhibits Th2 differentiation [106]; TRAF3 controls proximal T cell activation events and its absence in mice leads to elevated thymus derived T_reg cell frequencies [104]; FASLG is a marker for T cell activation and is expressed on Th1 cells [107, 108]; and SEMA7A and CD30 have been implicated in Th1 and Th17 differentiation [109, 110]. However, a role for these pathways impacting T_eff function in TB remains to be elucidated.

Evidence for exaggerated expression of cytokines that counterbalance T_reg function

It is well recognized that proinflammatory cytokines can suppress the generation and function of T_reg cells. By directly comparing the transcriptome of T_reg‐resistant HLA‐DR⁺ effector CD4⁺ T cells isolated from TB subjects with that of the T_reg‐sensitive fraction depleted of HLA‐DR⁺ CD4⁺ T cells, we provide the first evidence that HLA‐DR⁺ T_effs from TB express a number of proinflammatory cytokines, including IL‐2, IFN‐γ, colony stimulating factor‐2 (CSF2), IL‐17A and IL‐22 ([64], Fig. 3c). This exaggerated cytokine profile was noted in T_effs stimulated with both Mtb antigen as well as polyclonal stimulation [64] and could be possibly responsible for counter‐regulation of T_reg‐mediated suppression pathways, as summarized in Fig. 2. Both IFN‐γ and IL‐17A, although crucial for Mtb control [111, 112], are also recognized to counter‐regulate T_reg development and function and their exaggerated expansion, therefore, could be one mechanism for T_eff resistance to T_reg control [113, 114, 115].

Signal strength

A third potentially important consideration in the mechanisms that underpin how activated, HLA‐DR⁺ T effectors become resistant to T_reg cells may be linked to the quality and strength of the primary signal that activates effector cells. The strength of the activating signal shapes the nature of the immune response, with high signal strength leading to Th1 and low signal strength to Th2, Tfh and memory T cell differentiation (reviewed in [116, 117]). Previous studies show that effectors activated by a very strong signal strength become refractory to suppression mediated by T_reg cell co‐culture of human CD25⁻ T_eff and autologous CD25⁺ T_reg resulted in suppression only when stimulated with soluble anti‐CD3 (weak TCR signal) and not when activated with plate‐bound anti‐CD3 (strong TCR signal) [118]. Whether this is pertinent in the context of TB remains to be tested. What has been demonstrated from mouse studies is that persistently activated CD4⁺ T cells specific for the secretory Mtb antigen early secretory antigenic target 6 (ESAT6), which is expressed in abundance throughout infection, fail to confer protection, whereas CD4⁺ T cells specific for an Mtb antigen that has more controlled expression, e.g. antigen 85B (Ag85B), can confer greater protection [119]. The failure of ESAT6‐specific cells to confer protection was linked to the fact that these cells are more exhausted and terminally differentiated; i.e. express higher killer cell lectin‐like receptor subfamily G member 1 (KLRG1), lower CCR7, CD127 and CD62L, compared to Ag85B‐specific cells [119]. Whether T_reg‐resistant HLA‐DR⁺ T_eff cells isolated from TB subjects arise due to persistent antigen stimulation and bear markers of exhaustion remains to be confirmed.

Summary and future directions

It appears now from studies in animal models and humans that in TB the role of T_regs, both nT_reg and antigen‐specific, has several dimensions. While T_regs might delay the appearance of protective Th responses, especially during the early stages of infection, their function in the chronic stage of TB disease is consistent with their known primary function that is linked to control of exaggerated inflammation which, if unchecked, can contribute to disease pathology [120, 121]. The immune response in TB is clearly disordered, and the theme of balance between protective and pathogenic responses has been visited in the past [122]. In fact, a balance between Th1/Th17 and immune‐regulatory responses is associated with better clearance of Mtb infection [123]. In this context, the expansion of HLA‐DR⁺ T_eff cells in TB is a probable marker for inflammation associated with enhanced disease risk [124]. It has now been demonstrated that this expanded subset exhibits resistance to suppression mediated by natural T_reg cells [64]. The putative role of proinflammatory cytokines (IFN‐γ, IL‐17A, IL‐2, CSF2 and IL‐22), β‐chemokines and PD‐1/PD‐L1 interactions in modulating T_eff resistance to T_reg suppression in TB has been identified (Fig. 2). This calls for further analysis of the mechanisms that are important in maintaining balance between inflammation and immune‐regulation in TB.

Disclosures

The authors declare that they have no competing interests.

Acknowledgements

We acknowledge the support to our work on T_reg function in TB by a Centre of Excellence grant to A. V. from the Department of Biotechnology, Govt. of India (no. BT/PR10394/MED/29/1128/2016). We acknowledge additional funding for sample collection and analysis by EC HORIZON2020 TBVAC2020 and EC FP7 EURIPRED (FP7‐INFRA‐2012 Grant Agreement no. 312661) and DBT‐NIH (BT/MB/Indo‐US/HIPC/2013) to A. V. We also wish to thank Dr Srabanti Rakshit for careful reading and editing of the review.

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PERMALINK

Emerging patterns of regulatory T cell function in tuberculosis

A Ahmed

A Vyakarnam

Summary

Regulatory T (T_reg) cells: a brief introduction

Fig. 1.

Table 1.

Table 2.

Table 3.

Tuberculosis

T_regs in TB

Acute phase of infection: an analysis of animal model studies suggests early expansion to be detrimental

Chronic phase: animal model studies show loss in T_reg frequency or failure to recruit T_regs to site of infection can be detrimental

Human studies

Chronic phase: novel qualitative studies of T_reg function in humans highlight emergence of T_reg‐resistant T effectors in chronic TB

Fig. 2.

Mechanisms that underpin T_reg dysregulation in TB

Evidence for altered expression of cell surface molecules on T_eff that are important for engaging with T_reg cells

Fig. 3.

Evidence for exaggerated expression of cytokines that counterbalance T_reg function

Signal strength

Summary and future directions

Disclosures

Acknowledgements

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Emerging patterns of regulatory T cell function in tuberculosis

A Ahmed

A Vyakarnam

Summary

Regulatory T (Treg) cells: a brief introduction

Fig. 1.

Table 1.

Table 2.

Table 3.

Tuberculosis

Tregs in TB

Acute phase of infection: an analysis of animal model studies suggests early expansion to be detrimental

Chronic phase: animal model studies show loss in Treg frequency or failure to recruit Tregs to site of infection can be detrimental

Human studies

Chronic phase: novel qualitative studies of Treg function in humans highlight emergence of Treg‐resistant T effectors in chronic TB

Fig. 2.

Mechanisms that underpin Treg dysregulation in TB

Evidence for altered expression of cell surface molecules on Teff that are important for engaging with Treg cells

Fig. 3.

Evidence for exaggerated expression of cytokines that counterbalance Treg function

Signal strength

Summary and future directions

Disclosures

Acknowledgements

References

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

Regulatory T (T_reg) cells: a brief introduction

T_regs in TB

Chronic phase: animal model studies show loss in T_reg frequency or failure to recruit T_regs to site of infection can be detrimental

Chronic phase: novel qualitative studies of T_reg function in humans highlight emergence of T_reg‐resistant T effectors in chronic TB

Mechanisms that underpin T_reg dysregulation in TB

Evidence for altered expression of cell surface molecules on T_eff that are important for engaging with T_reg cells

Evidence for exaggerated expression of cytokines that counterbalance T_reg function