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Cellular and Molecular (2018) 15, 216–225 & 2018 CSI and USTC All rights reserved 2042-0226/18 $32.00 www.nature.com/cmi

REVIEW

The crucial roles of Th17-related /signal pathways in M. tuberculosis infection

Hongbo Shen1 and Zheng W Chen2

Interleukin-17 (IL-17), IL-21, IL-22 and IL-23 can be grouped as T helper 17 (Th17)-related cytokines because they are either produced by Th17/Th22 cells or involved in their development. Here, we review Th17-related cytokines/Th17-like cells, networks/signals and their roles in immune responses or immunity against Mycobacterium tuberculosis (Mtb) infection. Published studies suggest that Th17-related pathways may be manipulated by Mtb microorganisms for their survival benefits in primary tuberculosis (TB). In addition, there is evidence that immune responses of the signal transducer and activator of 3 (STAT3) signal pathway and Th17-like T-cell subsets are dysregulated or destroyed in patients with TB. Furthermore, Mtb infection can impact upstream cytokines in the STAT3 pathway of Th17-like responses. Based on these findings, we discuss the need for future studies and the rationale for targeting Th17-related cytokines/signals as a potential adjunctive treatment. Cellular and Molecular Immunology (2018) 15, 216–225; doi:10.1038/cmi.2017.128; published online 27 November 2017

Keywords: immunotherapy; miRNA; STAT; Th17-related cytokines

INTRODUCTION affect the behavior of adjacent cells. In Mtb infection, the Tuberculosis (TB) is now one of 10 most frequent causes of complex interaction between the and pathogen death and the top killer in infectious diseases due to the HIV/ is closely related to the production of various levels of AIDS epidemics and the increased spread of multidrug- cytokines, which contribute to determining outcomes of the resistant TB (MDR-TB).1 Mycobacteria tuberculosis (Mtb), the infection.6 causative agent of TB, is an intracellular microorganism that T helper 17 (Th17)-related cytokines comprise - lives in and epithelial cells.2 Cell-mediated 17A (IL-17A)/IL-17F, IL-21, IL-22 and IL-23, which are immunity has a crucial role in the control of Mtb infection and produced by Th17/Th22 cells or involved in their development. ultimately determines whether Mtb infection is cleared, latent Th17 cells differentiate with the induction of IL-6, transform- or active with TB consequences. Approximately one-third of ing -β (TGF-β)andIL-1β and are expanded by the world's population has been infected by Mtb, but only IL-23 via the STAT3 signaling pathway.7 Th17 cytokines can be 5–10% of them will eventually become ill with TB.3 However, produced by CD4+ T, CD8+ T, γδ T, natural killer T (NKT) persons with compromised immune systems, such as those and NK cells and can regulate effector functions of other living with HIV, malnutrition or diabetes, have a much higher immune cells after Mtb infection.8 Cellular signal pathways of risk of developing TB.1 Th17-related cytokines may be key modulators of adaptive Although cellular immune responses can inhibit or limit immune responses.9 Th17-related cytokines can also trigger the bacterial growth, they can also damage host tissues. It is production of anti-microbial peptides involved in the defense therefore critical to maintain the cellular immune response against bacterial pathogens.9 balance.4 To achieve this balance, the host uses some strategies, In this article, we review Th17-related cytokines, networks/ such as producing cytokines, to monitor and mediate effector signals and their roles in immune responses or immunity cell function.5 Cytokines are important in and can against Mtb infection. We also outline studies showing how

1Unit of Anti-tuberculosis Immunity, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China and 2Department of Microbiology and Immunology and Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, IL 60612, USA Correspondence: Dr H Shen, PhD, Unit of Anti-tuberculosis Immunity, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, No. 320 Yueyang Road, Shanghai 200031, China. E-mail: [email protected] Received: 30 June 2017; Revised: 14 October 2017; Accepted: 15 October 2017 Roles of Th17-related cytokines/signal pathways in Mtb infection H Shen and ZW Chen

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Mtb microorganisms manipulate Th17-related cytokine path- structure.17 The sequence variant of IL-17F is also correlated ways and upstream cytokines of the STAT3 signal in primary with susceptibility to TB.22 Interestingly, we have recently TB. Furthermore, we discuss the evidence that immune demonstrated that IL-17F and IL-17A can induce the recall responses of the STAT3 signal pathway and Th17-like T-cell response and effector function of TB phosphoantigen-specific subsets are dysregulated or destroyed in patients with TB. Vγ2Vδ2 T cells after Bacillus Calmette–Guérin (BCG) immu- Finally, we discuss future studies in TB research. nization and Mtb infection in nonhuman primates,23 suggest- ing a role of IL-17 in adaptive γδ T-cell responses. TH17-RELATED CYTOKINES/TH17-LIKE CELLS AND THEIR ROLES IN MTB INFECTION Interleukin-21 IL-17 and Th17 cells Th17/22-like γδ T cells, which express the IL-17 family cytokines contain six members, IL-17A–17F. RORγt (retinoic acid -related orphan receptor-γt) and Among them, IL-17A and IL-17F share a similar structure IL-23R (IL-23 receptor), produce not only IL-17 and IL-22 but and have similar roles in the immune response against Mtb also IL-21 under the stimulation of IL-1β and IL-23; participa- 10,11 infection. The roles of other members of the IL-17 family tion of the T-cell receptor is not necessary.7 After stimulation are currently not known in Mtb infection. with Mtb antigens, NKT cells isolated from TB patients also In patients with chronic TB, IL-17A production appears to produced IL-21 and other cytokines such as IL-17, -γ be decreased. The production of IL-17A by peripheral blood (IFN-γ), -α (TNF-α) and IL-2.24,25 IL-21- mononuclear cells (PBMCs) isolated from chronic TB patients expressing NKT cells showed an effector memory phenotype fi is signi cantly lower than PBMCs isolated from healthy control and expressed CXCR5.25 However, the main sources producing ex vivo fi (HC) subjects. Under the puri ed derivative IL-21 are activated CD4+ T cells with the induction of Mtb- stimulation, PBMCs from TB patients also secrete lower levels specificpeptides.26 IL-21 signaling plays important roles in host of IL-17A than those isolated from HC subjects. The decrease resistance to Mtb infection.27 In TB patients, circulating levels in IL-17A production, correlated with the exhaustion of T cells, of IL-21 are significantly diminished compared with latent may be due to the overexposure to Mtb antigens and tuberculosis infection (LTBI) or HC individuals.27,28 hyperexpression of the exhausted marker programmed death- The IL-21/ IL-21R signaling pathway has pleiotropic effects 1(PD-1).12,13 Increased PD-1 expression appears to be relevant on immunity and has an important role in T-cell immune to the depressed production of IL-17A in TB because anti- responses against Mtb infection because it contributes to PD-1 antibodies can enhance IL-17A production by Mtb- augment CD8+ T-cell priming and improve T-cell accumula- stimulated CD4+ T cells of TB patients.14 Anti-TB therapy can tion in the , enhancing the production of effector decrease PD-1 expression and increase IL-17A production by 27 CD4+ T cells.15,16 cytokines. IL-21 signaling may also inhibit exhaustion of IL-17A is a protective cytokine against mycobacteria infec- T cells since more CD4+ and CD8+ T cells expressing T-cell tion in the host; suppressing IL-17A production will increase immunoglobulin and mucin domain 3 (TIM-3) and PD-1 are − − 12 TB susceptibility.17 In fact, there is a decreased risk for TB observed in chronically infected IL-21R / mice. These development related to the IL-17A–197A allele, AA genotype IL-21R KO mice show an increased susceptibility to Mtb and A carrier (AG/AA).18 IL-17A is involved in the formation infection, characterized by earlier mortality and higher lung 27 and stability of granulomas by increasing produc- bacterial burden compared with wild-type (WT) mice. tion, which helps recruit inflammatory cells migrating to the Circulating T follicular helper (Tfh) cells can also produce 29 Mtb-infected sites.10,19 TheimmunerecallresponseofCD4+ IL-21 and have important roles in immunity to infections. T cells producing IL-17 occurs simultaneously with the The frequencies of Tfh cell subsets induced by Mtb antigen are 30 expression of the of CXCL11, CXCL10 and significantly lower in TB patients than those in LTBI subjects. CXCL9 and facilitates pulmonary recruitment of Th1 cells Similarly, frequencies of antigen-induced IL-21-producing Tfh and anti-TB immunity.20 Virtually, IL-17RA, the A subset of cells are also obviously lower in TB patients, with diminished the IL-17A receptor, can mediate the expression of CXCL-1 circulating levels of IL-21.30 Although IL-21 is associated with and CXCL-5, which are important for recruiting the expansion of B cells and helps B cells secrete antibodies of moving to the lungs of Mtb-infected mice.21 Notably, when the immunoglobulin G (IgG) and IgA, it may also participate in IL-17A is knocked out in mice, granulomas in the local immune responses for fighting against Mtb infection.25 mycobacteria-infected lung fail to mature, and the expression of adhesion molecules of intercellular adhesion molecule-1 and IL-22 and Th22 cells lymphocyte function-associated antigen-1 decreases, which T cells and NK cells are the major sources of IL-22. leads to an impaired protective response.19 Furthermore, the Accumulating data suggest that Th17 and Th22 are two distinct adoptive transfer of γδ T cells, which are the dominating cell subsets in humans and nonhuman primates.31 In TB IL-17A-producing cells in the lung granuloma, can rebuild patients, the IL-22 concentration in the serum is lower than granuloma in the IL-17A knockout (KO) mice.19 that in LTBI subjects, and anti-TB treatment could enhance The immune protective role of IL-17F in Mtb infection is IL-22 antigen-specific responses in active TB patients.32–34 similar to IL-17A, which is 50% homologous to IL-17F in Although frequencies of Th22 cells in the blood of TB patients

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are low, the IL-22 protein level in bronchoalveolar lavage Interleukin-23 (BAL) fluid is high.35 IL-23 is a heterodimeric cytokine comprised of an IL-12B IL-22 induces the production of anti-bacterial peptides (IL-12p40) subunit and the IL-23A (IL-23p19) subunit, and its including β-, lipocalin and regenerating islet-3-γ from functional receptor includes IL-12Rβ1 and IL-23R. IL-23 is 20 lung epithelial cells and and macrophages to kill mainly produced by antigen-presenting cells. In vitro,Mtb pathogens.36 In addition, macrophages express the IL-22 can induce -derived dendritic cells (DCs) and human 47–49 In vivo receptor within TB granulomas in the lungs, and IL-22 alveolar macrophages to produce IL-23. ,the α can activate macrophages to mediate mycobacterial expression of IL-23 is enhanced in PBMCs in nonhuman control and induce TNF-α production (refs 31,37,38, data primates at the early stage of mycobacteria infection; later, its 50 not shown). expression decreases to the normal level. Moreover, levels of γ IL-12p40, one subunit of IL-23, are higher in the serum of TB Surprisingly, the productions of IL-22 and IFN- are 48,50 reciprocally related. The expression of IL-22 is significantly patients than in HCs and decrease after anti-TB treatments. IL-23 could mediate its effects on both innate and adaptive increased in the shortage of IFN-γ; likewise, the production of arms of the immune system that express the IL-23R.48 Th17 IFN-γ is enhanced when monoclonal anti-IL-22 antibodies cells are the representative T-cell subset that vigorously inhibit IL-22 signaling.39 For example, Vγ2Vδ2 T cells activated responds to IL-23.51 The IL-23/IL-17 axis appears to act as by phosphoantigen HMBPP ((E)-4-hydroxy-3-methyl-but-2- γ an important modulator of immune responses associated with enyl pyrophosphate) can increase IFN- production and all phases of Mtb infection, with protective roles reported in a downregulate a potential over-reactive IL-22 response in mouse TB model.20 fl 31 lymphocytes from BAL uid, blood and lymph nodes. The TCR γδ T cells can be one of the main sources of IL-17 γ production of endogenous IFN- by HMBPP-activated responding to IL-23 stimulation.52 Our studies recently showed γ δ V 2V 2 T cells appears to be the underlying mechanism since that IL-23 and other Th17-related cytokines can induce adding anti-IFN-γ-neutralizing antibody can abrogate or proliferation and expansion of Vγ2Vδ2 T cells in the presence reduce the capability of HMBPP-induced Vγ2Vδ2Tcellsto of HMBPP.23 Mycobacteria vaccination/infection of macaques decrease IL-22 production.40,41 Similarly, anti-IL-22 monoclo- enhances the ability of IL-23 to expand HMBPP-activated nal antibody treatment can increase the expression of IFN- Vγ2Vδ2 T cells, and those expanded cells have multieffector γ.39,42 IL-22-producing cells may regulate protection against functions for producing cytokines of IL-17, IL-22, IL-2 and Mtb infection. Primary Mtb infection in nonhuman primates IFN-γ.23 Autocrine production of IFN-γ and IL-2 can, in turn, induces significant increases in T cells, producing IL-22. enhance IL-23/HMBPP-stimulated recall-like expansion of Moreover, these IL-22-producing cells are more apparent in Vγ2Vδ2 T cells.23,53 The STAT3-dependent signal pathway is the lungs than in the lymphoid tissues and blood.31,40,43 With involved in the IL-23 expansion of Vγ2Vδ2Tcells.48,54,55 Data the help of confocal microscopy and immunohistochemistry, from studies using PBMCs of TB patients show that the IL-23- IL-22-producing T cells can be detected in situ in lung TB IL-17 axis is likely dysregulated or damaged by overexposure to 56,57 granulomas.44 Appreciable numbers of mature IL-22- stimulation of Mtb antigens in chronic infection. This will producing T cells in lung TB granulomas suggest that they be discussed in detail below. fi may have an important role in protective immune responses to In summary, these ndings demonstrate that Th17-related Mtb infection, despite the fact that an over-reactive IL-22 or cytokines and Th17/Th22 cells may be devoted to immune Th22 response may also contribute to TB pathology.31 The responses to Mtb infection and may be involved in protective hypothesis of protective IL-22/Th22 responses in TB is also immunity against primary Mtb infection. There are some experimental data implicating dysregulated immune responses supported by the observation that Th22 cells carrying of selected Th17-related cytokines in patients with TB. membrane-borne IL-22 and IL-22 released by NK cells from Mtb-infected individuals can inhibit the intracellular growth of MTB MICROORGANISMS MAY MANIPULATE TH17- 38,40 Mtb bacilli. RELATED CYTOKINE SIGNALING PATHWAYS FOR THEIR Moreover, the rs2227473 single-nucleotide polymorphism SURVIVING BENEFITS IN PRIMARY TB (SNP) in IL-22 is related to the risk of pulmonary TB, and the In the primary Mtb infection phase, STAT3 pathways are 45 fi G allele is the risk factor. This SNP may have a signi cant stimulated in phagocytes (monocytes/macrophages),58 but their role in the protective immune process against TB by affecting protective effects are suppressed by the products of Mtb and/or 45 the IL-22 expression of PBMCs. by immunosuppressive cytokines from Mtb-stimulated host in vivo 46 – Despite a lack of conclusive evidence, the above cells.59 61 The STAT3 pathway and Th17-related cytokines findings suggest that Th22 or IL-22 may contribute to appear to be influenced by Mtb infection in the following protection against Mtb infection.38,40,42 Currently, functions complex aspects. and dysfunctions of IL-22 and Th22 cells in human TB remain After infection, virulent Mtb organisms survive in phago- incompletely characterized. Further in-depth studies may help cytes, and Mtb antigens directly simulate the STAT3 signal elucidate the roles of IL-22/Th22 in anti-TB immunity or TB pathway to regulate host immunity. The early secreted anti- pathology. genic target of 6 kDa (ESAT-6) is an essential virulence factor,

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Figure 1 Primary Mtb infection exploits STAT3-dependent signals in phagocytes for bacterial survival benefits. (a) Mtb antigens ESAT-6 and α-crystalline 1 (Acr1) activate the STAT3 signal pathway to induce the production of IL-6 and IL-10 and inhibit the translocation of NF-κB, Akt and mTOR in phagocytes in primary Mtb infection. This also represses the expression/synthesis of iNOS and NO, favoring Mtb survival. (b) Mtb-induced IL-27 induces STAT3 and inhibits the production of TNF-α and IL-12 in activated macrophages. (c) IL-10 exerts its effects in a partly STAT3-dependent manner, inhibiting the production of C/EBP-beta, with potential enhancement of HIV-1 replication, as observed in THP-1 cells. (d) Mtb infection facilitates STAT3 expression and phosphorylation by decreasing the repression of miR-17. ESAT-6, early secreted antigenic target of 6 kDa; IL, interleukin; iNOS, inducible synthase; NO, nitric oxide; Mtb, Mycobacterium tuberculosis; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; STAT3, signal transducer and activator of transcription 3; TB, tuberculosis; TNF-α, tumor necrosis factor-α. stimulating macrophages to produce IL-6 via STAT3 activation Mtb infection, IL-10 levels and STAT3 and pSTAT3 expression (Figure 1).62 It induces phosphorylation and DNA binding of levels increase significantly in the first week. The production of STAT3, which can be blocked by STAT3 inhibitors.62 The IL-10 is strongly correlated with the expression of STAT3 and induced IL-6 is responsible for the suppression of Th1 pSTAT3 .67 In vitro, IL-10 can regulate the protective responses and the suppression of Mtb-infected and Mtb- phenotype in Mtb-infected phagocytes including monocyte- uninfected bystander responses to IFN-γ,which derived macrophages, phorbol myristate acetate-treated THP- induces autophagy in Mtb-infected macrophages.63,64 Mtb -1 cells and human alveolar macrophages.68 IL-10 plays its antigens expressed in latency, such as α-crystalline 1 (Acr1), immunosuppressive effects on this early response of Mtb- can also interfere with the differentiation of DCs by infected macrophages in a partly STAT3-dependent manner. targeting STAT3 pathways (Figure 1).65 Continuous activation The inhibitory activity of Mtb would be reversed when IL-10 is of STAT3 would inhibit the translocation of nuclear factor-κB neutralized through the addition of soluble IL-10 receptor.66 (NF-κB) in DCs treated by Acr1.65 Thus, Mtb in latently The interaction of Mtb with differentiating monocytes rapidly infected individuals could use these strategies to survive and activates the STAT pathway, which likely participates in IL-10 antagonize the attempts of eradication by the anti-TB immune .69 STAT3 activation leads to the inhibition of system. cytokines IL-6, IFN-γ, TNF-α and MIP-1β (macrophage Mtb infection induces the production of immunosuppressive inflammatory protein-1β).70 In the primary infection phase, cytokines including IL-10 to affect STAT3 activation.66 After STAT3 also represses the expression/synthesis of inducible

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nitric oxide synthase and nitric oxide, which are important subjects,48 although Mtb-stimulated monocytes from TB factors that kill intracellular Mtb.2,71 patients express similar amounts of IL-23p19 mRNA and Unlike virulent Mtb, the TB vaccine BCG can drive effective protein as those from LTBI subjects. Mtb-stimulated CD4+ Th1-cell responses dependent on Th17-related cytokines to T cells from TB patients express less IL-23R and pSTAT3 than defeat IL-10 inhibitory effects induced by bacteria. those from LTBI subjects.16 This may be correlated with highly -E2 induced by BCG promotes IL-10 expression expressed PD-1 because a blockade by anti-PD-1 antibodies while simultaneously inducing IL-23 production and differ- can enhance IL-23R and pSTAT3 expression and IL-17 entiation of Th17 cells. The ability of IL-17 to decrease IL-10 production by Mtb-stimulated CD4+ T cells from TB and increase IL-12 production admits the generation of patients.77 Anti-TB therapy can decrease PD-1 expression and protective Th1-cell responses and subsequent vaccine-induced increase the expression of IL-17, IFN-γ, pSTAT3 and IL-23R. protection against Mtb challenge. Thus, the IL-23/IL-17 path- Chronic TB may depress the STAT3 signal pathway, leading to way could overcome IL-10-mediated inhibition to drive Th1- a decrease in the expression of IL-23R and production of IL-17 cell responses.51 by CD4+ T cells in TB patients (Figure 2). IL-27, another immunosuppressive cytokine, can also mod- Interestingly, our recent studies in humans have shown that ulate the STAT3 pathway.72 In vitro, IL-27 induces STAT3 TB patients exhibit selective impairing of the IL-23 signal effect phosphorylation and inhibits activated macrophages to pro- on the TB phosphoantigen HMBPP-specific γδ T-cell subset, duce TNF-α and IL-12 and regulate the Th1 response during 72 with a consequence of IL-23-targeted exhaustion of Vγ2Vδ2 Mtb infection. Furthermore, IL-27 can modulate excessive 53,78,79 inflammation via a feedback mechanism.72,73 Whether this can T-cell responses. Such selective impairing of the IL-23 be observed in vivo remains to be investigated in TB. signaling effect can be linked to depressed expression and Mtb infection may manipulate or utilize the STAT3 pathway phosphorylation of STAT3 and the overexpression of antag- 60,61 by inducing the differentiation of monocytes toward an onizing factor SOCS3. The downregulation of the STAT3 γ δ immunosuppressive (M2-like) macrophage activation signal pathway in V 2V 2 T cells correlates with remarkable program.70 These M2-like macrophages are characterized by increases in two miRNAs targeting STAT3 (Figure 2). hsa- the phenotype of CD16+CD163+MerTK+pSTAT3+ and can miR-337-3p and hsa-miRNA-125b-5p are expressed much function as an immunomodulator.67 This process relies on higher in Vγ2Vδ2 T cells from TB patients compared STAT3 activation and shows a detrimental role in TB.67 There with those from HC subjects with a BCG vaccination is a significant connection between the progression of the history (Figure 2). Most strikingly, the downregulation of disease and the copiousness of the CD16+CD163+MerTK hsa-miR-337-3p and hsa-miRNA-125b-5p using an miRNA +pSTAT3+ cells.67 sponge allows for detectable recovery of IL-23-induced expan- Mtb infection could also regulate the STAT3 effect by sion of Vγ2Vδ2 T cells in TB patients and their effector mediating the expression of microRNAs (miRNAs) targeted on functions for producing anti-TB cytokines of IFN-γ and STAT3.55,74 Mtb infection causes the downregulation of IL-17A.53 miR-17 and corresponding upregulation of its target STAT3 By contrast, the IL-2 signaling pathway does not appear to be 74,75 to suppress autophagy, which has an important role in the disrupted in TB because IL-2+HMBPP still can expand 76 bacterial burden control. Forced expression of miR-17 Vγ2Vδ2 T cells in peripheral blood from TB patients.53,80 74 reduces the production of STAT3 and regulates autophagy. Although IL-2 synergizes or facilitates the IL-23-induced in vitro Thus, or animal studies demonstrate that during expansion of Vγ2Vδ2 T cells, the IL-2 blockade cannot primary TB, Mtb microorganisms can manipulate the STAT3 completely abrogate the IL-23-induced expansion.53 This fi pathway for their surviving bene ts using the following notion is also supported by the STAT3 blockade data demon- strategies: producing Mtb products, inducing immunosuppres- strating that STAT3 has an important role in the expansion of sive cytokine/inflammatory macrophage induction and altering – Vγ2Vδ2 T cells by IL-23, but not IL-2.80 82 It is interesting to specific miRNAs targeting STAT3. demonstrate that TB can selectively impair IL-23 signaling but γ δ 53,80 IMMUNE RESPONSES OF THE STAT3 PATHWAY AND spare IL-2 effects on V 2V 2 T cells. Such selective TH17-LIKE CELLS ARE DYSREGULATED OR impairing of the IL-23 effect may occur as a result of persistent γ δ DESTROYED IN TB PATIENTS exposure of V 2V 2 T cells to phosphoantigen HMBPP or In TB patients, the chronic Mtb infection appears to destroy IL-23 during chronic TB infection. the STAT3 signal pathway in T cells, leading to selective Unlike CD4+ T cells, TB-driven impairing of the IL-23- fi γ δ impairing of the signal effect of IL-23.53,59 IL-23 is a positive induced expansion of HMBPP-speci cV2V 2 T cells cannot regulator of the STAT3 signal pathway and can act on both the be explained by T-cell exhaustion linked to PD-1 signaling. differentiation of CD4 Th0 to IL-23R-expressing Th17 cells and Although Ab blocking of the PD-1 pathway can reverse the the maturation of γδ T cells, which constitutively express exhaustion of αβ T cells linked to PD-1 expression,83 this IL-23R and are important sources to produce IL-17.20 blockade cannot restore IL-23 induced expansion of Vγ2Vδ2 CD4 T cells of TB patients are demonstrated to secrete less T cells despite our use of two different sources of PD-1 Abs IL-17 under stimulation of Mtb than do those of LTBI capable of recovering from T-cell exhaustion.

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Figure 2 Responses of the STAT3 signal pathway and Th17-like T cells that are dysregulated or impaired in patients with TB. In TB patients, T-cell exhaustion coincides with a high expression of PD-1 and downregulation of the IL-23 receptor. Thus, stimulation with IL-23 and Mtb antigens cannot induce adequate expression of STAT3. The phosphorylation of STAT3 is also decreased. Mechanistically, two miRNAs targeting STAT3 are highly expressed, and they could inhibit the expression and phosphorylation of STAT3. Consequently, the production of IL-17 is reduced. IL, interleukin; miRNA, microRNA; Mtb, Mycobacterium tuberculosis; PD-1, programmed death-1; RORγt, retinoic acid receptor-related orphan receptor-γt; STAT3, signal transducer and activator of transcription 3; TB, tuberculosis; Th17, Thelper17.

MTB INFECTION REGULATES THE EXPRESSION OF from TB patients produce more TGF-β than those from LTBI UPSTREAM CYTOKINES IN THE STAT3 PATHWAY, under Mtb antigen stimulation. The overexpression of TGF-β DRIVING TH17-LIKE RESPONSES in TB patients appears to be transient, and the values return to β β Cytokines of TGF- , IL-6 and IL-1 are regulatory mediators normal ranges at the end of 3 months of treatment in upstream of the STAT3 pathway. These upstream cytokines sequential studies. Although TGF-β can act as an anti- fi have been shown to undergo signi cant changes in Mtb inflammatory cytokine, the immunological significance of infection, although it is unknown how each contributes to changes in this cytokine of TB patients remains to be dysregulation of Th17-like responses in TB. Below are the investigated. reported changes in these cytokines in Mtb infection, mostly in patients with TB. Interleukin-6 fl Transforming growth factor-β IL-6 could initiate early proin ammatory responses, such as to TGF-β belongs to the TGF superfamily produced by all white induce the differentiation of T cells producing IL-17. Com- blood cell lineages.84 Costimulation of TGF-β with IL-6 is pared with HC subjects, TB patients have higher baseline levels required for Th17 cell differentiation.85 The TGF-β1 content in of serum IL-6.87 Four months after anti-TB drug treatment, the serum of TB patients is higher than that in HC controls, IL-6 levels rapidly decrease and stabilize in TB patients. These and the serum level of TGF-β1 is directly related to the results indicate that IL-6 may participate in the regulation of bacterial load and radiological severity.86 Moreover, PBMCs immune responses to Mtb infection.87

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Interleukin-1β findings can indeed closely represent immune responses or IL-1β is part of an 11-member IL-1 cytokine family and signals immunopathogenesis occurring in the pulmonary compart- through IL-1R.88 IL-1β is mainly produced by monocytes and ment or lung tissue of TB patients. This is not a trivial question DCs and is vital to the Th17 response to Mtb.88 IL-1β functions because TB is a chronic, complex disease that is accompanied as the innate Th17-polarizing cytokine and determines the by pathological processes in the lung tissue. More investigations outcome of the Th17 response to Mtb and its antigen in the lung and pulmonary compartment of TB patients will 89 β fi fractions. The amounts of secreted IL-1 are signi cantly display many aspects distinct from what is observed in the 90 correlated with Th17 responses, and exogenous replenish- blood. In fact, there are compelling lines of evidence that Th17- β fi ment of IL-1 is suf cient to markedly increase the Th17 related cytokines and Th17-like cells are remarkably different 89 response by the Mtb cytoplasmic fraction. Moreover, the from those observed in the blood in TB.31,97 Thus, in-depth β receptor of IL-1 and IL-18 receptor engagement induce an studies using pulmonary compartment samples from TB fi 91,92 Mtb antigen-speci c Th1/Th17 immune response. patients are necessary. It would also be useful to conduct Notably, although these upstream cytokines of the STAT3 mechanistic studies of TB immunology/pathobiology in lungs pathway are highly expressed in TB patients, STAT3-driven using an improved nonhuman primate TB model mimicking immune responses of Th17 cells and dominant Ag-specific chronic TB in humans. Vγ2Vδ2 T-cell subsets are dysregulated or impaired. This may Th17-related cytokines could contribute to immune protec- be attributed to the dysfunction or destruction of the STAT3 tion against primary Mtb infection, and their expression levels pathway, which is characterized by decreases in expression and are decreased in TB patients. Such decreases may be related to phosphorylation of STAT3 and marked increases of micro- the exhaustion of T cells as a result of prolonged overexposure RNAs that downregulate STAT3, leading to no or a reduced to the stimulation of Mtb antigens in chronic infection. The response to IL-23 or Th17-related cytokines. production of Th17-related cytokines is dependent on the TH17-RELATED CYTOKINES IN TB PATHOLOGY STAT3 signal pathway, and this pathway is dysregulated or TB pathogenesis is critically related to the extent of damaged in TB infection, with decreases in the expression and inflammation.93 Therefore, Th17 responses in TB are pre- phosphorylation of STAT3 and marked increases in micro- sumed to participate in pathology according to their activities, RNAs targeting STAT3. Such dysregulated or deficient condi- such as recruitment and promoting inflammatory tions may provide a rationale for adjunctive replacement responses in infection sites,93,94 which will cause serious tissue treatment targeting Th17 responses. This notion is supported damage in redundancy neutrophils and high degrees of by recent reports demonstrating that treatments with IL-2 inflammation.93 Recently, it was reported that there are more and others can result in beneficial results for attenuating IL-17-producing T cells and IL-2- and IL-10-producing T cells chronic non-tuberculosis mycobacteria (NTM) pulmonary in the lung granulomas of latent Mtb-infected macaques with a disease.98–101 high risk of reactivation than those in low-risk animals Conversely, the overproduction of Th17-related cytokines in identified by positron emission tomography CT.95 Therefore, TB patients may be detrimental and contribute to TB high lung inflammation is associated with TB reactivation pathology. If advanced studies confirm that IL-22 or other from LTBI. related cytokines have an active role in TB pathology in the Moreover, IL-22 is also suggested to participate in inducing lungs, immune interventions controlling for the overproduc- TB pathology.96 IL-22 was readily identified in disease sites of tion of IL-22 or others may be explored as a potential pericardial and pleural effusions of human TB, and the levels of adjunctive host-directed therapy.13,42,91,96 IL-22 are associated with the levels of matrix metalloprotei- nase-9, which degrades the extracellular matrix components, CONFLICT OF INTEREST causing pathology.96 Because TB is a complex disease, cytokine- The authors declare no conflict of interest. induced protective or pathological consequences are critically related to the balance of hemostasis. Based on the present data, ACKNOWLEDGEMENTS the roles of Th17-related cytokines cannot be simply defined as This work was supported by the following research grants: The ‘good’ or ‘bad’. Further detailed study is necessary to describe National Key Research and Development Program of China the features of the development of these cytokines in local (2016YFA0502204); the National Institutes of Health R01 grants disease sites and define their roles in TB pathology or (NIH R01 HL64560/OD015092/HL129887 to ZWC). protection.

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