Immunol Res DOI 10.1007/s12026-015-8654-0

INTERPRETIVE SYNTHESIS REVIEW ARTICLE

T regulatory cells: Achilles’ heel of Mycobacterium tuberculosis infection? Om Parkash1 • Sonali Agrawal1 • M. Madhan Kumar2

Ó Springer Science+Business Media New York 2015

Abstract T regulatory cells (Treg) constitute a specialized subset of T cells that play a pivotal role in preventing the occurrence of autoimmune diseases by suppressing deleterious activities of immune cells. Contrarily, they can have adverse effect on immune response against infectious diseases where Treg weaken the host immunity leading to enhanced microbial load and thereby increase in severity of the disease. Here, we have attempted to review plethora of information documenting prevalence of Treg in tuberculosis (TB) and their involvement in progression and immunopathogenesis of the disease. Further, we have laid emphasis on the possible use of Treg as a biomarker for determining the TB treatment efficacy. Also, we have discussed the probable contribution of Treg in dampening the efficacy of BCG, the anti-TB vaccine. Finally, we have speculated some of the possible strategies which might be explored by exploiting Treg for enhancing the efficacy of TB management. Keywords Tuberculosis  Treg  Immunology  Biomarker  Treatment

& Om Parkash [email protected]; [email protected] 1

Department of Immunology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, TajGanj, Agra 282001, India

2

Department of Biochemistry, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, TajGanj, Agra 282001, India

Introduction Tuberculosis (TB) is a major health concern worldwide for mankind, from time immemorial. It is a pervasive, morbid disease and ranks second in leading cause of deaths among infectious diseases with a toll of about 1.5 million deaths and 9 million new cases as estimated in 2013 [1]. This aggravated burden is due to the emergence of multidrugresistant (MDR) TB, extensively drug-resistant (XDR) TB and HIV coinfection [2–5]. Mycobacterium tuberculosis (MTB), the etiological agent of TB, is a highly successful intracellular pathogen which primarily infects lungs. Once infected, majority of the individuals develop latent TB due to persistence of MTB for years or decades and a relatively small proportion (5–10 %) of infected people will develop active TB disease [6]. The probability of developing active TB is much higher among people infected with HIV or in immunocompromised individuals. Despite the global efforts to reduce the burden of TB, the number of TB cases and deaths due to TB remains very large which may be due to lack of (i) efficient diagnostic tools, (ii) potential anti-TB vaccine and (iii) short-course treatment regimen (since longer treatment durations are liable to result in noncompliance and thereby emergence of resistant strains). These lacunae in the management of TB can be overcome by in-depth understanding of immunological aspects involved in the dynamic interplay between host and the pathogen. On invasion, MTB elicits both innate and adaptive immune responses in host. The innate immune response elicited by MTB involves professional phagocytes including macrophages, monocytes, dendritic cells (DCs) and neutrophils [7]; multiple bacterial pattern recognition receptors such as toll-like receptors (TLRs) [8–10]; nucleotide-binding oligomerization domain protein 2 (NOD2)

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[11, 12]; natural killer (NK) cells [13]; and complement system [14]. These innate immune components, on stimulation, induce the expression of pro-inflammatory cytokines, chemokines and cellular adhesion receptors that contribute to local and systemic immune cell activation and proliferation. On failing of the innate immunity to eliminate MTB, adaptive immunity takes over to combat the infection. Adaptive/cell-mediated immunity (CMI) is critical for effective protection against MTB. The pathogen triggers the immune system, wherein CD4? and CD8? T cells eliciting Th1-type immunity expand and respond to the assault [15]. The activated Th1 cells produce IFN-c which activates the microbicidal mechanism of macrophages to eliminate MTB [16]. Apart from IFN-c, other inflammatory cytokines like TNF-a, IL-1, IL-6, IL-12 are up-regulated as a response to MTB and they wreak havoc in the host by causing tissue damage and enhancing lung pathology. In order to ameliorate the pathology, the immune homeostatic mechanism brings in Treg to the rescue. Treg act swiftly in suppressing T effector (Teff) cell activation and expansion and nullifying pro-inflammatory cytokines in order to bring down the enhanced immunemediated damage [17]. In this process, Treg favor the survival of MTB. An imbalance in maintenance of immune homeostasis or Treg:Teff ratio may lead to chronic inflammation or autoimmunity [18]. Hence, manipulation of Treg may pave way for efficient management of TB and a proper understanding of their biology is a prerequisite for developing any strategies for the control of this disease. This review focuses on the role played by Treg in TB pathogenesis, mechanisms adopted by Treg in bringing about homeostasis and the possible use of these cells as a marker in TB treatment monitoring. Lastly, the review also focuses on new avenues which can be embarked upon for exploiting Treg in TB management and the possible caveats associated with such approaches.

Treg: a prelude

function of CD4?CD25? Treg [20]. This marker has been included with the conventional markers CD4?CD25? for better defining this subset. The classification of Treg into natural (nTreg) and induced (iTreg) is based on the development of nTreg (FoxP3?) in the thymus, and iTreg are induced during the immune response to pathogen in peripheral lymphoid organs (spleen, lymph nodes, gut-associated lymphoid tissue). The iTreg are further classified based on the secretion of the cytokines TGF-b and IL-10. Tr1 subsets produce IL-10 and are FoxP3-, whereas Th3 subsets produce TGF-b predominantly and are FoxP3? [21]. Certain CD4?FoxP3? cells have been found to express low CD127 (IL-7 Ra), and the same has been used as a marker for Treg (CD4?FoxP3?CD127lo) [22]. Recently, a unique population of inducer Treg has been reported which express the marker CD39 (ectonucleoside triphosphate diphosphohydrolase 1) [23]. Together with CD25, cells expressing this marker have been categorized into CD39?CD25- effector cells and CD39?CD25? regulatory cells. Treg that are CD39- also exist, and it has also been observed by Fletcher et al. [24] that cells which are CD4?CD25highCD39- induce suppression of proliferation but produce IL-17. Contrarily, CD4?CD25highCD39? Treg suppressed IL-17 production as well as proliferation. Predominantly, CD4? subset of Treg has been widely studied in various disease settings, but not CD8? Treg. CD39 appears to be another preferential marker of CD8? Treg which suppresses CD4? Th1 immune response through the generation of adenosine [25]. A subset of natural CD8? Treg, expressing FoxP3 and CTLA-4 (cytotoxic T lymphocyte-associated antigen-4), mediates suppression of IFN-c production and proliferation of CD4? T cells in contact-dependent manner. Additionally, several other markers like CD45RO, CD45RB, glucocorticoid-induced TNFR-related protein (GITR), OX-40 (CD134), folate receptor-4 (FR4), CD62L, CD44, CD28, CD26 and chemokine receptors (CCR7, CXCR3 and CXCR4) have also been used by various investigators to define the Treg [26]. But these markers are not widely used in TB for defining Treg because of their relatively less specificity. Various phenotypes of Treg studied in TB [25, 27–33] are depicted in Table 1.

Conventional Treg and associated markers Although Treg have been extensively studied, still the markers that define this subset of immune cells are obscure and no consensus has been reached on this till date. The conventional marker used by many studies is CD25, but it has also been found to be expressed by Teff cells and is not unique to this subset. Although CD25? is widely being used as marker for mice, in humans, CD25hi is considered more appropriate [19]. The transcription factor FoxP3 has been shown to be involved in programming the development and

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Non-conventional Treg Other subsets of Treg include: (i) CD8?CD28- potently suppresses immune response by secreting IL-10 [34]. (ii) cd CD4-CD8- (double-negative) T cells with regulatory profile in TB have been illustrated by their production of IL-10 [35]. However, these subsets have not been explored much because of their prevalence in very low numbers (0.8–1 % of human peripheral blood CD3? cells).

Immunol Res Table 1 Various Treg phenotypes reported in tuberculosis Subsets

Phenotypes

References

CD4? Treg

CD4?CD25high, CD4?CD25?FoxP3?, CD4?CD25highFoxP3?

Guyot-Revol et al. [27], Pang et al. [28]

CD4?CD25?GITR?, CD4?CD25?FoxP3?CD223?, CD4?CD25?FoxP3?CD223?IL-10?

Ordway et al. [29]

CD4?FoxP3?, CD4?FoxP3?ICOS?, CD4?FoxP3?PD-1?

Scott-Browne et al. [30]

CD4?CD25hiCD39?,CD4?CD25hiCD127-

Chiacchio et al. [31]

CD3?CD4?CD25highCD127low, CD4?CD25highCD127lowCD161?, CD4?CD25highCD127low CD39?, CD4?CD25highCD147??

Feruglio et al. [32]

CD8?CD28-

He et al. [33]

CD8?CD25?

Boer et al. [25]

CD8? Treg

CD8?CD25?FoxP3? CD8?CD25?FoxP3?CD39? CD8?CD25?FoxP3?CD39?LAG-3?CCL4?

Suppressive mechanisms Treg are known to suppress proliferation and activation of T cells, NK cells, NKT cells, monocytes, macrophages, DCs, B cells and eosinophils. They suppress the immune responses via multiple mechanisms (Fig. 1), including those that are contact-dependent and others that are mediated by soluble factors (or contact-independent) [36]. (i) Treg primarily influence the activation status of antigenpresenting cells (APCs). CTLA-4, a homologue of CD28 and a key molecule of Treg for their suppressive action, depletes or down-modulates the expression of co-stimulatory molecules CD80/CD86 by a process called transendocytosis. Consequently, CD28 co-stimulation of T cells is inhibited and thereby leads to suppression of T cellmediated immune response [37, 38]. (ii) Another contactdependent mechanism for immunosuppression has also been documented wherein indoleamine 2,3-dioxygenase (IDO), induced by CTLA-4, prevents T cell proliferation by depleting tryptophan (an essential amino acid) in local tissue microenvironment. Further, catabolism of tryptophan generates immunotoxic kynurenines which in turn causes apoptosis of Teff cells [39, 40]. Additionally, tryptophan catabolites induce conversion of peripheral CD4?CD25naive T cells to CD4?CD25? Treg. (iii) Treg deprive Teff cells from IL-2 by depleting the cytokine (IL-2) through binding to constitutively highly expressed IL-2 receptors on Treg. Subsequently, this leads to apoptosis of IL-2-deprived Teff cells [41]. (iv) LAG-3 (lymphocyte-activating gene-3) mediates immune regulation at the level of DCs. During this immune-regulatory process, LAG-3 transmembrane protein, expressed on Treg, interacts with MHCII on DCs. This interaction inhibits activation and maturation of DCs through ERK (extracellular signalregulated kinases)-mediated signaling pathway at the level

of SHP-1 (Src homology domain 2-containing tyrosine phosphatase-1) and thereby suppresses immunostimulatory capacity of DCs [42, 43]. (v) In contact-independent Tregmediated immunosuppression, increased levels of IL-10, TGF-b and IL-35 play a significant role in inhibiting T cell proliferation by providing anti-inflammatory milieu [44– 46]. (vi) An ATP-hydrolyzing ectoenzyme (CD39) catalyzes the conversion of ATP to AMP. The AMP thus produced would further metabolically be broken down by CD73 to adenosine which is known to be an important mediator for T cell suppression [23]. (vii) Very recently, Treg have been reported to employ miRNA-containing exosome-mediated gene silencing to suppress Teff cells. This phenomenon regulates Th1-mediated immunity either by proapoptotic or by anti-proliferative effect [47]. (viii) Perforin/granzyme-A/B-dependent T cell suppression, wherein perforin creates pores in cell membrane and serine protease granzyme-A/B, produced by Treg, is involved in direct killing of CD4? effector cells by apoptosis [48].

Treg and TB pathogenesis Treg and the infection site: granuloma M. tuberculosis, the causative agent of TB makes its way into human body via respiratory tract, when aerosolized MTB bacilli enter pulmonary alveoli. TB infection begins with the ingestion of tubercle bacilli by alveolar phagocytic cells such as macrophages and DCs. The phagocytosed bacilli are destroyed by lysosomal enzyme on phagosome– lysosomal fusion, but the bacilli inhibit this fusion and replicate within the macrophages. This uncontrolled growth of tubercle bacilli in the phagocytes, usually, results

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Fig. 1 Immunosuppressive mechanisms of CD4? Treg. DC dendritic cell, CTLA-4 cytotoxic T lymphocyte antigen-4, LAG-3 lymphocyte activation gene-3, ITAM immunoreceptor tyrosine-based activation

motif, Teff effector T cells, AMP adenosine monophosphate, ATP adenosine triphosphate, TGF-b transforming growth factor-b

in their apoptosis [49–51]. Also, MTB-infected phagocytes release pro-inflammatory cytokines which recruit more macrophages, monocytes and DCs. The immune and nonimmune cells aggregate together, and the bacteria get sequestered into a granulomatous structure [52]. Further, to keep a check on immunopathogenesis due to overt immune response against MTB, Treg infiltrate the site of infection [30, 53–55]. The infected phagocytes and accumulated Treg in the lesion produce IL-10 which in turn inhibits protective immune response by directly acting on antigenpresenting cells (APCs) such as macrophages and DCs [56]. During the initial stage of infection, bacillary growth restriction is mediated by innate immune cells which apart from mononuclear phagocytes also include the polymorph neutrophils. The recruitment of neutrophils to the site of infection has been reported to be mediated by Treg (through CXCL8 signaling pathways) [57]. The adaptive immunity sets in, only when the MTB-infected DCs carry the antigen to lymph node (LN), which is marked by the

priming of T cells in lymph nodes before their response in the infection site, i.e., lung [58]. This migration of DCs from lungs to LN occurs between 8 and 11 days after infection, and the role of Treg in mediating this delay is still not clear. The presentation of MTB antigens by DCs to naı¨ve T cells converts them to Teff cells, but this priming process is delayed by Treg at the LN. This subsequently affects and delays the migration of Teff cells (CD4? and CD8?) to lung. Arrival of Teff cells in the lungs brings about marked inflammation which is counterbalanced by Treg. Thus, Treg act as checkpoint in three stages: blocking effector cell responses in the lung, inhibiting priming and differentiation of T cells in the lymph node and inhibiting migration of activated T cells to the lung. As the inflammation progresses due to bacterial overload, the granuloma turns necrotic and finally caseates releasing bacteria into the damaged airways and expelled through coughing by the host for continuing transmission cycle. Besides CD4? and CD8? T cells, accumulation of

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increased frequency of FoxP3? Treg has also been reported in the lymphocytic layer of the granuloma in pulmonary TB and TB lymphadenitis [30, 53, 54]. Another recent report reinforces this fact, wherein the investigators have shown LAG-3 expression to be elevated significantly in granuloma indicating the presence of Treg along with NK cells in this immune confinement [59]. Accumulation and up-regulated numbers of Treg within the granuloma support the hypothesis that Treg may act locally to suppress immune activation and can also potentiate the persistence of bacteria. Significantly higher frequency of FoxP3? Treg has been observed among patients with cavitary TB than in non-cavitary TB patients. This substantiates that Treg are present throughout the ‘journey of granuloma’—from solid granuloma to necrotic till it turns to caseating. This tempts us to speculate that Treg might be one of the factors which might compromise granuloma and help the pathogen in continuing its transmission cycle, and it thus plays a prime role in pathogenesis. Treg and MTB persistence Treg have also been shown to play a crucial role in persistence of MTB in the host (Fig. 2). Although the mechanisms of their persistence have not been elucidated, some of the plausible mechanisms which have been propounded include: (i) MTB modulates infected APCs which induces secretion of CCL22 and CCL17 chemokines by APCs, leading to migration of Treg to the site of infection. Furthermore, the expansion of these migrated Treg is

Fig. 2 Various mechanisms employed by Treg toward suppression of T cell-mediated immunity and aiding in persistence of MTB. DC dendritic cell, TolDC tolerised DC, IL-10 interleukin-10, IL-12 interleukin-12, Treg T regulatory cells, nTregs natural Tregs, iTregs

promoted by MTB which induces increased expression of PD-L1 on DCs and the interaction of PD-1 on Treg with PD-L1 enhances their expansion [60–62]. (ii) An upregulation of IL-10 producing Tr1 (iTreg) is induced by immature DCs, and the immunosuppressive milieu thus have inhibitory effect on proliferation of Th1 cells. After invasion of lungs by MTB, the bacilli may be engulfed by immature DCs which in turn may tolerise the latter. These tolerised DCs after reaching the LN may create immunosuppressive milieu by producing IL-10, TGF-b and IL-35 [38, 63, 64]. (iii) Following MTB infection, both Th1 effector cells and Treg proliferate in the lymph node. On arrival of infected DCs to the lymph nodes, Treg with CTLA-4 and lymphocyte function-associated antigen-1 (LFA-1) expression out-compete the Teff cells in aggregating around DCs. This interaction between available Treg and DCs may down-modulate the expression of costimulatory molecules: CD80/86 [65, 66]. The depletion of co-stimulatory molecules in this way may dampen the activation of Teff cells, which indirectly turns the balance in favor of Treg proliferation. (iv) Constitutive expression of high-affinity IL-2 receptor makes Treg more efficient in consuming IL-2. This Treg-induced cytokine deprivation suppresses the proliferation and triggers the apoptosis of Teff cells [41]. (v) Some reports suggest that IL-12 is required for high T-bet (transcription factor) expression in Treg [67]. Higher T-bet expression would promote more expression of the chemokine receptor CXCR3 on Treg, which further may help in migration of Treg to site of infection. (vi) It is also observed that FoxP3? T cell

induced Tregs, Teff effector T cells, CTLA-4 cytotoxic T lymphocyte antigen-4, PD-1 programmed cell death 1, PD-L1 programmed cell death-ligand 1

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(nTreg) switches their trafficking/chemokine receptors and migration behavior during their development in the thymus and in secondary lymphoid tissues. Interestingly, this switching of chemokine receptor profile of nTreg is highly robust, compared with that of conventional CD4? T cells [68]. Hence, this early homing and rapid increase in frequency of Treg at the infection site may be another mechanism for dampening T cell response during infection. Whatever may be the mechanism for generation of Treg, their prevalence at the site of infection, could imbalance the existing homeostasis between Teff and Treg. Thus, Treg may contribute toward dampening of CMI, thereby resulting in progressive TB. Treg and dissemination of MTB Apart from causing infection at the site, MTB migrates to extra-pulmonary spaces being carried by APCs and establishes infection at those sites. The APCs present the antigen to CD4?, CD8? cells and activate them into Teff. The immune response against MTB in these sites by Teff is dampened by Treg, and this aids in persistence of MTB. Thus, Treg also play a role in dissemination of the disease to other sites. The critical role of Treg in restraining the Th1-mediated cellular immunity and thereby resulting in dissemination of TB has been evaluated among patients with extra-pulmonary TB and miliary TB. Several studies demonstrated an increase in Treg cell frequency and FoxP3 mRNA both peripherally and at the site of disease in persons with active extra-pulmonary TB (including patients with tuberculous pleurisy, bone or joint TB, meningeal TB and genitourinary TB) and disseminated TB [27, 33, 69]. Similarly, the enrichment of Treg as well as elevation of IL-10 in peripheral blood and pathologic site [pleural fluid and bronchoalveolar lavage (BAL)] has also been reported in miliary TB patients [70]. Treg in animal models In mice (Table 2), rapid expansion of Treg severely impedes preventive immunity by down-modulating Th1-mediated immunity and thereby prevents the sterile eradication of infection [29, 71]. Treg have also been demonstrated to exacerbate TB infection with significant accumulation in lungs and pulmonary lymph nodes of mice. To determine the significant role of Treg in modulating immune response against MTB, several studies have been carried out by Treg cell depletion approaches where effective elimination of Treg in mice significantly decreased the bacterial burden in the lungs [30]. In contrast to this, inactivating Treg (by anti-CD25mAb) improved Th1 protective immune responses modestly but did not have an effect on pathogen load or pathogen clearance [72,

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73]. In non-human primates (Macaques), an increasing frequency of Treg (lungs and blood) has been observed in those animals which developed active disease after mycobacterial challenge [54]. These studies reinforce the fact that Treg aggravate the pathology by inhibiting MTB clearance and paralyzing Th1 immunity. Nevertheless, Treg inactivation strategies need to be refined, since targeting CD25 alone cannot yield desired results due to the reasons: (1) The use of anti-CD25 antibody can deplete not only CD25? Treg but also CD25-expressing Teff, and (2) regulatory subsets that are CD25- will still persist after anti-CD25 treatment. Such CD25- cells would continue suppressing the immune processes. Hence, refining of the strategy must consider other Treg subsets and Teff also for achieving the desired outcome. Treg and clinical scenario The involvement of Treg in suppression of effector immune response in various human diseases like autoimmune diseases (myasthenia gravis [74], rheumatoid arthritis [75] and idiopathic juvenile arthritis [76]); infectious diseases (hepatitis B [77], hepatitis C [78], HIV/AIDS [79]); atopic dermatitis [80]; and cancer [81] is well established. However, information regarding the role of Treg in TB disease progression started emerging from 2006 onward [27]. The elevation of Treg and their role in TB pathogenesis have been evaluated in human samples (Table 2). In the initial study on Treg in humans by Guyot-revol, CD4?CD25high cells were found to be elevated with a concomitant increase in FoxP3 expression in pulmonary TB as well as extra-pulmonary TB patients’ naive for antitubercular treatment (ATT) [27]. The role of Treg in depressing T cell-mediated immune response has further been evaluated by investigating the down-modulation of HBHA (heparin-binding hemagglutinin)-induced IFN-c secretion in PBMCs of patients with active TB. In this study, in vitro depletion of CD4?CD25high Treg leads to enhanced IFN-c secretion in TB patients which was found to be similar to that in latent TB patients [82]. Further, the involvement of Treg in active disease has been validated on different subsets of Treg where Chiacchio et al. [31] reported higher percentage of CD4?CD25highCD39? and CD4?CD25highCD127- Treg in PBMCs along with higher release of IL10 and TGF-b in culture supernatant of TB patients when compared to healthy donors. Further, the lung compartment has also been evaluated for enhanced levels of Treg, by demonstrating enrichment of FoxP3? cells in BAL of TB patients [83]. An increased proportion of CD4? and CD8? Treg double positive for CD25 and FoxP3 has been detected in patients with MDR-TB [84]. In patients with cavitary MDR-TB, increased proportion of CD4?CD25high and

Immunol Res Table 2 Studies on Treg in tuberculosis Relevant findings

Organism

References

First study regarding involvement of Treg in tuberculosis: A threefold increase in frequency of CD4?CD25high T cells was observed along with an increase in FoxP3 expression in TB patients at disease sites

Human

Guyot-Revol et al. [27]

Reported failure of immune cells in achieving ‘sterile’ clearance of tubercle bacilli due to the expansion of CD4?CD25? Treg which down-modulate immune responses

Mice

Kursar et al. [71]

Rapid expansion of CD4?CD25?FoxP3?CD223?IL-10? Treg subset causes decline in the early immune response against HN878 infection and reduction in IFN-c-secreting CD4? T cells

Mice

Ordway et al. [29]

Depletion of CD4?CD25high T cells resulted in fivefold increase in IFN-c response to HBHA in an in vitro study with PBMCs of patients with active TB

Human

Hougardy et al. [82]

On aerosol infection with MTB, a significant accumulation of Treg was observed within lungs and pLNs. Further, upon depletion of FoxP3? cells, nearly tenfold reduction of bacterial load was observed

Mice

Scott-Browne et al. [30]

Inactivation of natural Treg, through anti-CD25 mAb treatment led to increased numbers of antigen-responsive lymphocytes and the earlier appearance of IFN-c and IL-2-producing lymphocytes in the spleen and IL-2 producing lymphocytes from the lungs after BCG challenge. However, pathogen clearance and pathology during the acute phase of the infection remained unaffected

Mice

Quinn et al. [72]

Patients with active TB have shown higher percentage of CD4?CD25hi?CD39? and CD4?CD25hi?CD127- Treg with significantly higher release of IL-10 and TGF-b in cell culture supernatant

Human

Chiacchio et al. [31]

Significantly higher frequency of CD4?CD25?FoxP3? Treg and predominantly released IL-10, possessing suppressive property against T cell proliferation, was observed in miliary TB patients

Human

Sharma et al. [70]

With the development of active disease, monkeys experienced increased frequency of CD4?FoxP3? Treg among PBMCs

Macaque

Green et al. [54]

Elevated population of CD4?CD25? and CD4?CD25?FoxP3? Treg were observed in TB patients than those in recovered TB patients and healthy controls. An increase in levels of TGF-b along with restraining Th1-mediated cellular immunity was also reported

Human

Pang et al. [28]

HBHA heparin-binding hemagglutinin antigen, PBMCs peripheral blood mononuclear cells, HN878 hypervirulent strain of MTB, pLNs pulmonary lymph nodes

CD4?CD25?FoxP3? Treg is observed which decreases significantly at 6 months postoperatively [85]. The function of Treg in immunopathogenesis is substantiated by a recent study on patients with cavitary TB, wherein a higher frequency of CD4?CD25?FoxP3? Treg along with elevated expression of TGF-b and decreased IFN-c levels has been observed when compared to non-cavitary TB patients [28]. Treg apart from playing a role in active TB are also implicated in latent TB infection. A subset of Treg CD4?CD25?CD127- has been found to be elevated in latent TB individuals that decreased after prophylactic therapy (with isoniazid and rifampicin), but the other subset CD4?CD25?FoxP3? increased after therapy [86]. Thus, different subsets of Treg may play a role in latency or active TB. The progression of an individual from latency to active TB may also depend on the intricate balance between the different subset of Treg. In a study [83], it has been observed that elevated Treg subset (CD4?CD25high CD127-) is associated with a concomitant increase in the

cytokines IL-10 and TGF-b. Similarly, in another study [28], elevated levels of CD4?CD25?FoxP3? subset are associated with an increase in the cytokine TGF-b and decreased IFN-c. So, at different stages of prophylactic therapy, it would be worth to consider targeting the immune suppressive cytokines to get the desired beneficial therapeutic effect. A detailed study of the TB infection showed the main antagonist of Th1 cells to be the Th2 type of cells which neutralized the protective immune responses. Later studies implicated the role of regulatory cells along with Th2 cells in dampening protective immunity. The omnipresence of Treg at all the sites where the pathogen is present during TB points out to the fact that in the process of maintaining homeostasis, they work together with pathogen in its persistence and spread to other sites. They also play a very important role in continuation of the transmission cycle of the bacterium for its better survival. Strategies aimed at targeting the pathogen must consider this subset of immune cells and/or Treg-associated cytokines (IL-10 and TGF-b)

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meticulously because gross depletion of these subsets may be detrimental to the host in exacerbating pathology as well as inducing autoimmune responses [87].

Treg as a possible biomarker toward treatment monitoring To delineate the status of Treg during treatment in TB patients, frequency of these cells during and after treatment has been analyzed by many studies (Table 3). Several studies observed a rapid decline in frequency of CD4?CD25?FoxP3? Treg (ex vivo as well as in vitro stimulation with antigens) during the course of anti-TB treatment for pulmonary TB [33, 88, 89]. This decline is gradual, and it can be exploited as a biomarker for predicting treatment efficacy. Individuals showing a contrarily increasing level of Treg even after treatment have also been reported by a study along with those who show decreasing levels of Treg after treatment when compared to levels before ATT [90]. Thus, the use of the marker for monitoring treatment must be done in pan-HLA (human leukocyte antigen) populations as HLA might be a factor which induces differential responses among the patient groups. The use of the marker for monitoring can be tailor-made according to the HLA types after delineating the differentially responding HLA types and the Treg responses. Regarding the immunosuppressive cytokine produced by Treg, a positive correlation has been found between the declining Treg and reduced IL10 production, whereas an increase in levels of effector cytokine (IFN-c) has been observed in culture supernatant at various time points of chemotherapy [88, 89]. Therefore, these studies substantiate the use of multiple biomarkers to monitor early treatment response. Similarly, a significant reduction in frequency of various Treg subsets (CD4?CD25?FoxP3?, CD4?CD25high

CD127low, CD4?CD25highCD147??, CD4?CD25high low ? CD127 CD161 ) has been observed on completion (6 months) of anti-TB therapy in blood as well as diseased sites (pleural fluid) of extra-pulmonary patients [32, 91]. This steady decline of Treg along with treatment substantiates their use as a biomarker for monitoring treatment efficacy in the broad spectrum of TB ranging from pulmonary to extra-pulmonary. Nevertheless, these cells can be exploited for their use even in smear negative, culture negative as well as smearnegative culture-positive cases for early reporting of treatment efficacy. Thus, these studies provide a lead for exploring the possibility of using Treg as a biomarker for monitoring treatment efficacy as the currently used sputum microscopy suffers from many drawbacks (inability to monitor treatment efficacy in extra-pulmonary cases, non-sputum producers and smear- and culture-negative cases; need for 10,000 bacilli/ml of sputum for detection, etc.)

Treg and efficacy of vaccines Bacille Calmette–Gue´rin (BCG), the anti-TB vaccine, is one of the most widely used vaccines for pulmonary TB. BCG, with an efficacy of 0–80 %, is known to have protective effect against meningitis and disseminated TB in children [92]. Despite its lower efficacy, BCG is still being used worldwide for more than 90 years. In an endemic area, it can be speculated that pre-exposure to mycobacterial antigens (present in environment) may induce and sensitize Treg in the host. These sensitized Treg may further be stimulated by vaccination with BCG and subsequently by MTB infection. Eventually, all this induction may result in generation of large pool of Treg which in turn could down-modulate the efficacy of BCG vaccine [93]. On the other hand, in regions where environmental

Table 3 Summary of various studies showing effect of anti-TB treatment on regulatory T cells in humans Relevant findings

References

The elevation in frequency of CD4?CD25? Treg sustained even on completion of anti-TB therapy for 6 months

Ribeiro-Rodrigues et al. [90]

Reported significant decline in elevated levels of CD4?CD25? and CD4?CD25?FoxP3? Treg after 1 month of anti-TB treatment

He et al. [33]

The increased levels of CD?CD25?FoxP3? and CD4?CD25hiFoxP3? Treg declined progressively during 2 months of anti-TB treatment

Jackson-Sillah et al. [89]

Following anti-TB chemotherapy, CD4?CD25?FoxP3? Treg number declined gradually along with reduction in IL-10 levels

Singh et al. [88]

Frequency of CD4?CD25?FoxP3? Treg in blood as well as pleural fluid reduced significantly after completion of anti-TB therapy for 6 months

Arram et al. [91]

Study revealed an initial transient increase of CD4? Treg followed by a decrease toward baseline levels at week 24 (6 months) of treatment

Feruglio et al. [32]

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mycobacteria are not prevalent, prior induction of Treg will be lacking which may not dampen the BCG vaccine efficacy. This might be the reason for the success of BCG vaccine in these regions. Treg are known to not only exacerbate the TB by suppressing the immune response during active infection, but also add toward making it endemic by dampening the vaccine efficacy. Recently, the involvement of Treg toward dampening the protective efficiency of anti-TB vaccine has been reported. Jaron et al. [94] showed that depletion of CD4? Treg significantly improves protective capacity of BCG vaccine. Similar results were obtained on boosting the BCG vaccine with AMM [Ag85B–Mpt64190-198– Mtb8.4], and a subunit vaccine has been demonstrated to enhance the protective efficacy of BCG by significantly down-regulating the CD4? Treg [95]. In contrast to these, Boer and his co-workers demonstrated significantly higher CD8? Treg enrichment in PBMCs, compared to CD4? Treg, may have possible negative impact on vaccine-generated immunity [25]. So, vaccine designing methodologies must consider suppression of different subset of Treg for enhancing vaccine efficacy as well as search for epitopes from MTB antigens which will selectively suppress Treg by binding to their T cell receptors (TCRs). Such a strategy will prove to be a success even in endemic regions, where BCG vaccine is a failure when administered alone. Since antigen-specific Treg suppression can target Treg and can generate memory cells, pathogen assault subsequently may also be efficiently tamed by the immune system and enhanced response will lead to rapid clearance of the pathogen.

Perspectives Treg play a critical role in preventing autoimmunity by dampening self-reactive immune responses. During infectious diseases, Treg protect the host by avoiding deleterious immune reactions which otherwise may lead to tissue damage. On the other hand, Treg inhibit pathogen clearance (by suppressing the immunity) from the host leading to disease progression [30, 96, 97]. Though several reports have emerged pointing out the role of Treg in progression and determining severity of TB, many aspects of TB immunity (at the level of Treg) still remain unexplored. Detailed studies on this line may help in formulating strategies for prevention and management of TB in a refined manner. A specific biomolecule that can reliably differentiate Treg and Teff cells is very much required. This may lead toward developing monoclonal antibodies against such biomolecules to modulate the effect of these cells, specifically. Also, exploring cytokines, chemokines and pharmaceutical/chemical compounds having differential

effects on Treg and Teff cells may open avenues to develop therapeutic reagents to suppress or enhance, selectively, the response of these cells. This eventually may help in maintaining the immune homeostasis. Recently, a promising attempt in this direction has been made with IL-2 (in macaques) where simultaneous expansion of Treg and Teff cells allowed these cells to act in concert to attenuate severe lung damages or lesions in infections [98]. In another recent study, it has been shown that small moleculedirected immunotherapy used a combination of suplatast tosylate (inhibitor of Th2 differentiation) and D4476 (inhibitor of Treg differentiation) in mice which were BCG vaccinated and challenged with H37RV, and the capacity of BCG to protect against TB was found to be enhanced [99]. Such immunotherapeutic approaches enhance host-protective immune responses and significantly reduce bacterial burden. Therefore, immunotherapeutic strategies aimed at Treg also appear to be promising and may help in improving favorable host responses against TB. In TB, the adaptive immune response initiates after 8–11 days of infection. However, to date, the role of Treg in mediating this delay and facilitating MTB replication is still unknown. In order to halt progression of disease and collateral damage to tissues, it is imperative to determine biochemical pathways involved in expansion of Treg during early phase of infection. Blocking of such pathways could help in controlling the infection in the early phase and siRNA technology to silence the relevant genes [100, 101] involved in these pathways may prove to be useful. In the late phase, iTreg can also be targeted to maintain homeostasis and to enhance Th1 responses to accelerate disease resolution. Lastly, knowledge about BCG-/MTBderived biomolecules which discreetly activate Treg compared to Teff cells is still obscure. Moreover, the ability of Treg to respond to specific antigen during infection as well as studies on whether Treg recognize pathogen-derived antigen or not has not been explored in depth. But, a recent study has shown that both FoxP3? Treg and Teff cells recognize same MTB-specific ESAT-64–17:I-Ab and Ag85B240–254:I-Ab epitopes and expand in lymph node [102]. Although TCRs expressed by conventional T cells and Treg arise from separate lineages, but they share some dominant TCRs, this might be the reason for their capacity to react to same foreign antigens. Hence, determining such epitopes which are specifically recognized by Treg could help in developing effective vaccines, better therapeutic approaches and efficient drug-targeting modalities. Keeping in view, the hurdles in effective TB disease treatment (non-compliance of patients during treatment, emergence of drug-resistant MTB strains, absence of treatment markers for extra-pulmonary cases, etc.) monitoring of treatment efficacy in TB patients are yet another field of research interest. Conventionally available

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tool, i.e., sputum microscopy, is not efficient for treatment monitoring in TB patients, since it suffers from inherent demerits. Hence, there is an urgent need of alternative better tool for this purpose. Regarding Treg, there are several reports [32, 33, 88–91] pointing out their decline along with treatment. Hence, establishing of Treg as a biomarker for treatment monitoring appears to be promising and deserve further attention. Nonetheless, Treg can be considered as double-edged sword, which on one hand is beneficial as it suppresses the deleterious activities of immune cells that could be detrimental to the host tissues, while on the other hand, Treg facilitate, due to their immunosuppressive behavior, the progression of TB and in persistence of MTB making the disease chronic. Therefore, strategies need to be explored to manipulate Treg with extreme caution to extract its beneficial aspects and nullify its detrimental effects on the host.

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14. Acknowledgments Thanks to Department of Science and Technology, Government of India, for providing Inspire fellowship to Ms. Sonali Agrawal. Thanks to NJIL & OMD, Agra, for routine facilities. Thanks to Infolep, The Netherlands, for providing scientific literature.

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Conflict of interest The authors declare that they have no conflicts of interest.

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References 1. World Health Organization (WHO). Global tuberculosis report 2014. Geneva: WHO/HTM/TB/2014.08. 2014. http://www.who. int/tb/publications/global_report/en/. 2. Dooley SW, Jarvis WR, Martone WJ, Snider DE Jr. Multidrugresistant tuberculosis. Ann Intern Med. 1992;117(3):257–9. doi:10.7326/0003-4819-117-3-257. 3. Villarino ME, Geiter LJ, Simone PM. The multidrug-resistant tuberculosis challenge to public health efforts to control tuberculosis. Public Health Rep. 1992;107(6):616–25. 4. Shah NS, Wright A, Bai GH, Barrera L, Boulahbal F, Martı´nCasabona N, et al. Worldwide emergence of extensively drugresistance tuberculosis. Emerg Infect Dis. 2007;13(3):380–7. doi:10.3201/eid1303.061400. 5. Koenig R. Drug resistant tuberculosis in South Africa, XDR TB and HIV prove a deadly combination. Science. 2008;319(5865):894–7. doi:10.1126/science.319.5865.894. 6. Dheda K, Schwander SK, Zhu B, van Zyl-Smit RN, Zhang Y. The immunology of tuberculosis: from bench to bedside. Respirology. 2010;15(3):433–50. doi:10.1111/j.1440-1843.2010. 01739.x. 7. van Crevel R, Ottenhoff TH, van der Meer JW. Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev. 2002;15(2): 294–309. doi:10.1128/CMR.15.2.294-309.2002. 8. Abel B, Thieblemont N, Quesniaux VJ, Brown N, Mpagi J, Miyake K, et al. Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice. J Immunol. 2002;169(6):3155–62. doi:10.4049/jimmunol.169.6. 3155. 9. Scanga CA, Bafica A, Feng CG, Cheever AW, Hieny S, Sher A. MyD88-deficient mice display a profound loss in resistance to

123

18.

19.

20.

21. 22.

23.

24.

25.

Mycobacterium tuberculosis associated with partially impaired Th1 cytokine and nitric oxide synthase 2 expression. Infect Immun. 2004;72(4):2400–4. doi:10.1128/IAI.72.4.2400-2404. 2004. Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A. TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med. 2005;202(12):1715–24. doi:10.1084/jem.20051782. Ferwerda G, Girardin SE, Kullberg BJ, Le Bourhis L, de Jong DJ, Langenberg DM, et al. NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog. 2005;1(3):279–85. doi:10.1371/journal.ppat. 0010034. Gandotra S, Jang S, Murray PJ, Salgame P, Ehrt S. Nucleotidebinding oligomerization domain protein 2-deficient mice control infection with Mycobacterium tuberculosis. Infect Immun. 2007;75(11):5127–34. doi:10.1128/IAI.00458-07. Morikawa F, Nakano A, Nakano H, Oseko F, Morikawa S. Enhanced natural killer cell activity in patients with pulmonary tuberculosis. Jpn J Med. 1989;28(3):316–22. doi:10.2169/ internalmedicine1962.28.316. Schlesinger LS, Bellinger-Kawahara CG, Payne NR, Horwitz MA. Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J Immunol. 1990;144(7):2771–80. Schaible UE, Collins HL, Kaufmann SH. Confrontation between intracellular bacteria and the immune system. Adv Immunol. 1999;71:267–377. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993;178(6):2249–54. doi:10.1084/jem.178.6.2249. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61. doi:10.1126/science.1079490. Berod L, Puttur F, Huehn J, Sparwasser T. Tregs in infection and vaccinology: heroes or traitors? Microb Biotechnol. 2012;5(2):260–9. doi:10.1111/j.1751-7915.2011.00299.x. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4?CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167(3):1245–53. doi:10.4049/jimmunol.167.3.1245. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4?CD25? regulatory T cells. Nat Immunol. 2003;4(4):330–6. doi:10.1038/ni904. Corthay A. How do regulatory T cells work? Scand J Immunol. 2009;70(4):326–36. doi:10.1111/j.1365-3083.2009.02308.x. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4? Treg cells. J Exp Med. 2006;203(7):1701–11. doi:10.1084/jem.20060772. Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, et al. Expression of ectonucleotidase CD39 by Foxp3? Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 2007;110(4):1225–32. doi:10. 1182/blood-2006-12-064527. Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O’Farrelly C, et al. CD39 ? FoxP3 ? Regulatory T cells suppress pathogenic Th17 cells and are impaired in Multiple Sclerosis. J Immunol. 2009;183:7602–10. doi:10.4049/jimmunol. 0901881. Boer MC, van Meijgaarden KE, Bastid J, Ottenhoff TH, Joosten SA. CD39 is involved in mediating suppression by Mycobacterium bovis BCG-activated human CD8?CD39? regulatory T cells. Eur J Immunol. 2013;43(7):1925–32. doi:10.1002/eji. 201243286.

Immunol Res 26. Jonuleit H, Schmitt E. The regulatory T cell family: distinct subsets and their interrelations. J Immunol. 2003;171(12): 6323–7. doi:10.4049/jimmunol.171.12.6323. 27. Guyot-Revol V, Innes JA, Hackforth S, Hinks T, Lalvani A. Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis. Am J Respir Crit Care Med. 2006;173(7):803–10. doi:10.1164/rccm.200508-1294OC. 28. Pang H, Yu Q, Guo B, Jiang Y, Wan L, Li J, et al. Frequency of regulatory T-cells in the peripheral blood of patients with pulmonary tuberculosis from shanxi province, china. PLoS ONE. 2013;8(6):e65496. doi:10.1371/journal.pone.0065496. 29. Ordway D, Henao-Tamayo M, Harton M, Palanisamy G, Troudt J, Shanley C, et al. The hypervirulent Mycobacterium tuberculosis strain HN878 induces a potent TH1 response followed by rapid down-regulation. J Immunol. 2007;179(1):522–31. doi:10. 4049/jimmunol.179.1.522. 30. Scott-Browne JP, Shafiani S, Tucker-Heard G, Ishida-Tsubota K, Fontenot JD, Rudensky AY, et al. Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J Exp Med. 2007;204(9):2159–69. doi:10.1084/jem.20062105. 31. Chiacchio T, Casetti R, Butera O, Vanini V, Carrara S, Girardi E, et al. Characterization of regulatory T cells identified as CD4?CD25highCD39? in patients with active tuberculosis. Clin Exp Immunol. 2009;156(3):463–70. doi:10.1111/j.1365-2249. 2009.03908.x. 32. Feruglio SL, Tonby K, Kvale D, Dyrhol-Riise AM. Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of active Mycobacterium tuberculosis infection. Clin Exp Immunol. 2015;179(3):454–65. doi:10.1111/ cei.12468. 33. He XY, Xiao L, Chen HB, Hao J, Li J, Wang YJ, et al. T regulatory cells and Th1/Th2 cytokines in peripheral blood from tuberculosis patients. Eur J Clin Microbiol Infect Dis. 2010;29(6):643–50. doi:10.1007/s10096-010-0908-0. 34. Jarvis LB, Matyszak MK, Duggleby RC, Goodall JC, Hall FC, Gaston JS. Autoreactive human peripheral blood CD8? T cells with a regulatory phenotype and function. Eur J Immunol. 2005;35(10):2896–908. doi:10.1002/eji.200526162. 35. Pinheiro MB, Antonelli LR, Sathler-Avelar R, Vitelli-Avelar DM, Spindola-de-Miranda S, Guimara˜es TM, et al. CD4-CD8ab and cd T cells display inflammatory and regulatory potentials during human tuberculosis. PLoS ONE. 2012;7(12):e50923. doi:10.1371/journal.pone.0050923. 36. Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T. Regulatory T cells: how do they suppress immune responses? Int Immunol. 2009;21(10):1105–11. doi:10.1093/intimm/dxp095. 37. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332(6029):600–3. doi:10.1126/science.1202947. 38. Perruche S, Zhang P, Liu Y, Saas P, Bluestone JA, Chen W. CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med. 2008;14(5):528–35. doi:10.1038/ nm1749. 39. Puccetti P, Grohmann U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation. Nat Rev Immunol. 2007;7(10):817–23. doi:10.1038/nri2163. 40. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zetachain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176(11):6752–61. doi:10.4049/jimmunol.176.11. 6752. 41. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4?CD25?FoxP3? regulatory T cells induce cytokine deprivation-

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

mediated apoptosis of effector CD4? T cells. Nat Immunol. 2007;8(12):1353–62. doi:10.1038/ni1536. Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21(4):503–13. Liang B, Workman C, Lee J, Chew C, Dale BM, Colonna L, et al. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol. 2008;180(9):5916–26. doi:10.4049/jimmunol.180.9.5916. Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med. 1999;190(7):995–1004. doi:10.1084/jem.190.7.995. Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlowCD4? T cells. J Exp Med. 1996;183(6):2669–74. doi:10.1084/jem.183.6.2669. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566–9. doi:10. 1038/nature06306. Okoye IS, Coomes SM, Pelly VS, Czieso S, Papayannopoulos V, Tolmachova T, et al. MicroRNA-containing T-regulatory-cellderived exosomes suppress pathogenic T helper 1 cells. Immunity. 2014;41(1):89–103. doi:10.1016/j.immuni.2014.05.019. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004;21(4):589–601. Molloy A, Laochumroonvorapong P, Kaplan G. Apoptosis, but not necrosis, of infected monocytes is coupled with killing of intracellular bacillus Calmette-Gue´rin. J Exp Med. 1994;180(4):1499–509. doi:10.1084/jem.180.4.1499. Keane J, Balcewicz-Sablinska MK, Remold HG, Chupp GL, Meek BB, Fenton MJ, et al. Infection by Mycobacterium tuberculosis promotes human alveolar macrophages apoptosis. Infect Immun. 1997;65(1):298–304. Placido R, Mancino G, Amendola A, Mariani F, Vendetti S, Piacentini M, et al. Apoptosis of human monocytes/macrophages in Mycobacterium tuberculosis infection. J Pathol. 1997;181(1):31–8. Reece ST, Kaufmann SH. Floating between the poles of pathology and protection: can we pin down the granuloma in tuberculosis? Curr Opin Microbiol. 2012;15(1):63–70. doi:10. 1016/j.mib.2011.10.006. Rahman S, Gudetta B, Fink J, Granath A, Ashenafi S, Aseffa A, et al. Compartmentalization of immune responses in human tuberculosis: few CD8? effector T cells but elevated levels of FoxP3? regulatory T cells in the granulomatous lesions. Am J Pathol. 2009;174(6):2211–24. doi:10.2353/ajpath.2009.080941. Green AM, Mattila JT, Bigbee CL, Bongers KS, Lin PL, Flynn JL. CD4? regulatory T cells in a cynomolgus macaque model of Mycobacterium tuberculosis infection. J Infect Dis. 2010;202(4): 533–41. doi:10.1086/654896. Welsh KJ, Risin SA, Actor JK, Hunter RL. Immunopathology of postprimary tuberculosis: increased T-regulatory cells and DEC205-positive foamy macrophages in cavitary lesions. Clin Dev Immunol. 2011;2011:307631. doi:10.1155/2011/307631. Fiorentino DF, Zlotnik A, Vieira P, Mosmann TR, Howard M, Moore KW, et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991; 146(10):3444–51. Himmel ME, Crome SQ, Ivison S, Piccirillo C, Steiner TS, Levings MK. Human CD4?FOXP3? regulatory T cells produce CXCL8 and recruit neutrophils. Eur J Immunol. 2011;41(2):306–12. doi:10.1002/eji.201040459.

123

Immunol Res 58. Wolf AJ, Desvignes L, Linas B, Banaiee N, Tamura T, Takatsu K, et al. Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. J Exp Med. 2008;205(1): 105–15. doi:10.1084/jem.20071367. 59. Phillips BL, Mehra S, Ahsan MH, Selman M, Khader SA, Kaushal D. LAG3 expression in active Mycobacterium tuberculosis infections. Am J Pathol. 2014. doi:10.1016/j.ajpath.2014. 11.003. 60. Periasamy S, Dhiman R, Barnes PF, Paidipally P, Tvinnereim A, Bandaru A, et al. Programmed death 1 and cytokine inducible SH2-containing protein dependent expansion of regulatory T cells upon stimulation with Mycobacterium tuberculosis. J Infect Dis. 2011;203(9):1256–63. doi:10.1093/infdis/jir011. 61. Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJ. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3?CD4? regulatory T cells. Proc Natl Acad Sci USA. 2008;105(27):9331–6. doi:10.1073/pnas. 0710441105. 62. Trinath J, Maddur MS, Kaveri SV, Balaji KN, Bayry J. Mycobacterium tuberculosis promotes regulatory T-cell expansion via induction of programmed death-1 ligand 1 (PD-L1, CD274) on dendritic cells. J Infect Dis. 2012;205(4):694–6. doi:10.1093/ infdis/jir820. 63. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711. doi:10. 1146/annurev.immunol.21.120601.141040. 64. Maldonado RA, von Andrian UH. How tolerogenic dendritic cells induce regulatory T cells. Adv Immunol. 2010;108: 111–65. doi:10.1016/B978-0-12-380995-7.00004-5. 65. Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S. Foxp3? natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci USA. 2008;105(29):10113–8. doi:10.1073/pnas. 0711106105. 66. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87. doi:10. 1016/j.cell.2008.05.009. 67. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol. 2009;10(6):595–602. doi:10.1038/ni.1731. 68. Lee JH, Kang SG, Kim CH. FoxP3? T cells undergo conventional first switch to lymphoid tissue homing receptors in thymus but accelerated second switch to nonlymphoid tissue homing receptors in secondary lymphoid tissues. J Immunol. 2007;178(1):301–11. doi:10.4049/jimmunol.178.1.301. 69. Qin XJ, Shi HZ, Liang QL, Huang LY, Yang HB. CD4?CD25? regulatory T lymphocytes in tuberculous pleural effusion. Chin Med J (Engl). 2008;121(7):581–6. 70. Sharma PK, Saha PK, Singh A, Sharma SK, Ghosh B, Mitra DK. FoxP3? regulatory T cells suppress effector T-cell function at pathologic site in miliary tuberculosis. Am J Respir Crit Care Med. 2009;179(11):1061–70. doi:10.1164/rccm.200804-529OC. 71. Kursar M, Koch M, Mittru¨cker HW, Nouailles G, Bonhagen K, Kamradt T, et al. Cutting Edge: Regulatory T cells prevent efficient clearance of Mycobacterium tuberculosis. J Immunol. 2007;178(5):2661–5. doi:10.4049/jimmunol.178.5.2661. 72. Quinn KM, McHugh RS, Rich FJ, Goldsack LM, de Lisle GW, Buddle BM, et al. Inactivation of CD4?CD25? regulatory T cells during early mycobacterial infection increases cytokine production but does not affect pathogen load. Immunol Cell Biol. 2006;84(5):467–74. doi:10.1111/j.1440-1711.2006.01460. x. 73. Ozeki Y, Sugawara I, Udagawa T, Aoki T, Osada-Oka M, Tateishi Y, et al. Transient role of CD4?CD25? regulatory T

123

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

cells in mycobacterial infection in mice. Int Immunol. 2010;22(3):179–89. doi:10.1093/intimm/dxp126. Balandina A, Le´cart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4?CD25? T cells in the thymus of patients with autoimmune myasthenia gravis. Blood. 2005;105(2):735–41. doi:10.1182/blood-2003-11-3900. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFa therapy. J Exp Med. 2004;200(3):277–85. doi:10.1084/jem.20040165. Mo¨tto¨nen M, Heikkinen J, Mustonen L, Isoma¨ki P, Luukkainen R, Lassila O. CD4?CD25? T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol. 2005;140(2):360–7. doi:10.1111/j.1365-2249.2005. 02754.x. Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 2005;41(4):771–8. doi:10.1002/ hep.20649. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, et al. An immunomodulatory role for CD4?CD25? regulatory T lymphocytes in hepatitis C virus infection. Hepatology. 2004;40(5): 1062–71. doi:10.1002/hep.20454. Weiss L, Donkova-Petrini V, Caccavelli L, Balbo M, Carbonneil C, Levy Y. Human immunodeficiency virus-driven expansion of CD4?CD25? regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood. 2004;104(10):3249–56. doi:10.1182/blood-2004-01-0365. Ou LS, Goleva E, Hall C, Leung DY. T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol. 2004;113(4):756–63. doi:10.1016/j. jaci.2004.01.772. Fiore F, Nuschak B, Peola S, Mariani S, Muraro M, Foglietta M, et al. Exposure to myeloma cell lysates affects the immune competence of dendritic cells and favors the induction of Tr1like regulatory T cells. Eur J Immunol. 2005;35(4):1155–63. doi:10.1002/eji.200425093. Hougardy JM, Place S, Hildebrand M, Drowart A, Debrie AS, Locht C, et al. Regulatory T cells depress immune responses to protective antigens in active tuberculosis. Am J Respir Crit Care Med. 2007;176(4):409–16. doi:10.1164/rccm.200701-084OC. Semple PL, Binder AB, Davids M, Maredza A, van Zyl-Smit RN, Dheda K. Regulatory T cells attenuate mycobacterial stasis in alveolar and blood-derived macrophages from patients with tuberculosis. Am J Respir Crit Care Med. 2013;187(11): 1249–58. doi:10.1164/rccm.201210-1934OC. Geffner L, Basile JI, Yokobori N, Sabio Y Garcı´a C, Musella R, Castagnino J, et al. CD4(?) CD25(high) forkhead box protein 3(?) regulatory T lymphocytes suppress interferon-c and CD107 expression in CD4? and CD8? T cells from tuberculous pleural effusions. Clin Exp Immunol. 2014;175(2):235–45. doi:10.1111/cei.12227. Wu YE, Peng WG, Cai YM, Zheng GZ, Zheng GL, Lin JH, et al. Decrease in CD4?CD25?FoxP3? Treg cells after pulmonary resection in the treatment of cavity multidrug-resistant tuberculosis. Int J Infect Dis. 2010;14(9):e815–22. doi:10.1016/ j.ijid.2010.04.005. Wergeland I, Assmus J, Dyrhol-Riise AM. T regulatory cells and immune activation in Mycobacterium tuberculosis infection and the effect of preventive therapy. Scand J Immunol. 2011;73(3):234–42. doi:10.1111/j.1365-3083.2010.02496.x. Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol. 2004;4(11):841–55. doi:10.1038/ nri1485.

Immunol Res 88. Singh A, Dey AB, Mohan A, Sharma PK, Mitra DK. Foxp3? regulatory T cells among tuberculosis patients: impact on prognosis and restoration of antigen specific IFN-c producing T cells. PLoS ONE. 2012;7(9):e44728. doi:10.1371/journal.pone. 0044728. 89. Jackson-Sillah D, Cliff JM, Mensah GI, Dickson E, Sowah S, Tetteh JK, et al. Recombinant ESAT-6-CFP10 fusion protein induction of Th1/Th2 cytokines and FoxP3 expressing Treg cells in pulmonary TB. PLoS ONE. 2013;8(6):e68121. doi:10.1371/ journal.pone.0068121. 90. Ribeiro-Rodrigues R, Resende Co T, Rojas R, Toossi Z, Dietze R, Boom WH, et al. A role for CD4?CD25? T cells in regulation of the immune response during human tuberculosis. Clin Exp Immunol. 2006;144(1):25–34. doi:10.1111/j.13652249.2006.03027.x. 91. Arram EO, Hassan R, Saleh M. Increased frequency of CD4?CD25?FoxP3? circulating regulatory T cells (Treg) in tuberculous patients. Egypt J Chest Dis Tuberc. 2014;63:167–72. doi:10.1016/j.ejcdt.2013.10.013. 92. Colditz GA, Berkey CS, Mosteller F, Brewer TF, Wilson ME, Burdick E, et al. The efficacy of bacillus Calmette–Gue´rin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics. 1995;96(1Pt1):29–35. 93. Parkash O. How to avoid the impact of environmental mycobacteria towards the efficacy of BCG vaccination against tuberculosis? Int J Mycobacteriol. 2014;3:1–4. doi:10.1016/j. ijmyco.2014.01.006. 94. Jaron B, Maranghi E, Leclerc C, Majlessi L. Effect of attenuation of Treg during BCG immunization on anti-mycobacterial Th1 responses and protection against Mycobacterium tuberculosis. PLoS ONE. 2008;3(7):e2833. doi:10.1371/journal.pone. 0002833. 95. Luo Y, Jiang W, Da Z, Wang B, Hu L, Zhang Y, et al. Subunit vaccine candidate AMM down-regulated the regulatory T cells and enhanced the protective immunity of BCG on a suitable schedule. Scand J Immunol. 2012;75(3):293–300. doi:10.1111/j. 1365-3083.2011.02666.x.

96. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL. CD4?CD25? regulatory T cells control Leishmania major persistence and immunity. Nature. 2002;420(6915):502–7. doi:10. 1038/nature01152. 97. Berod L, Stu¨ve P, Varela F, Behrends J, Swallow M, Kruse F, et al. Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity. PLoS ONE. 2014;9(7):e102804. doi:10. 1371/journal.pone.0102804. 98. Chen CY, Huang D, Yao S, Halliday L, Zeng G, Wang RC, et al. IL-2 simultaneously expands Foxp3? T regulatory and T effector cells and confers resistance to severe tuberculosis (TB): implicative Treg-T effector cooperation in immunity to TB. J Immunol. 2012;188(9):4278–88. doi:10.4049/jimmunol. 1101291. 99. Bhattacharya D, Dwivedi VP, Kumar S, Reddy MC, Van Kaer L, Moodley P, et al. Simultaneous inhibition of T helper 2 and T regulatory cell differentiation by small molecules enhances Bacillus Calmette-Guerin vaccine efficacy against tuberculosis. J Biol Chem. 2014;289(48):33404–11. doi:10.1074/jbc.M114. 600452. 100. Zhang HH, Fei R, Xie XW, Wang L, Luo H, Wang XY, et al. Specific suppression in regulatory T cells by Foxp3 siRNA contributes to enhance the in vitro anti-tumor immune response in hepatocellular carcinoma patients. Beijing Da Xue Xue Bao. 2009;41(3):313–8. 101. Zheng X, Koropatnick J, Chen D, Velenosi T, Ling H, Zhang X, et al. Silencing IDO in dendritic cells: a novel approach to enhance cancer immunotherapy in a murine breast cancer model. Int J Cancer. 2013;132(4):967–77. doi:10.1002/ijc.27710. 102. Shafiani S, Dinh C, Ertelt JM, Moguche AO, Siddiqui I, Smigiel KS, et al. Pathogen-specific Treg cells expand early during Mycobacterium tuberculosis infection but are later eliminated in response to Interleukin-12. Immunity. 2013;38(6):1261–70. doi:10.1016/j.immuni.2013.06.003.

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T regulatory cells: Achilles' heel of Mycobacterium tuberculosis infection?

T regulatory cells (Treg) constitute a specialized subset of T cells that play a pivotal role in preventing the occurrence of autoimmune diseases by s...
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