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. 2017 Nov 27;15(3):216–225. doi: 10.1038/cmi.2017.128

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

Hongbo Shen 1,*, Zheng W Chen 2
PMCID: PMC5843620  PMID: 29176747

Abstract

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 cytokine 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 transcription 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.

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

Introduction

Tuberculosis (TB) is now one of 10 most frequent causes of death and the top killer in infectious diseases due to the HIV/AIDS epidemics and the increased spread of multidrug-resistant TB (MDR-TB).1 Mycobacteria tuberculosis (Mtb), the causative agent of TB, is an intracellular microorganism that lives in macrophages and lung epithelial cells.2 Cell-mediated immunity has a crucial role in the control of Mtb infection and ultimately determines whether Mtb infection is cleared, latent or active with TB consequences. Approximately one-third of the world's population has been infected by Mtb, but only 5–10% of them will eventually become ill with TB.3 However, persons with compromised immune systems, such as those living with HIV, malnutrition or diabetes, have a much higher risk of developing TB.1

Although cellular immune responses can inhibit or limit bacterial growth, they can also damage host tissues. It is therefore critical to maintain the cellular immune response balance.4 To achieve this balance, the host uses some strategies, such as producing cytokines, to monitor and mediate effector cell function.5 Cytokines are important in cell signaling and can affect the behavior of adjacent cells. In Mtb infection, the complex interaction between the immune system and pathogen is closely related to the production of various levels of cytokines, which contribute to determining outcomes of the infection.6

T helper 17 (Th17)-related cytokines comprise interleukin-17A (IL-17A)/IL-17F, IL-21, IL-22 and IL-23, which are produced by Th17/Th22 cells or involved in their development. Th17 cells differentiate with the induction of IL-6, transforming growth factor-β (TGF-β) and IL-1β and are expanded by IL-23 via the STAT3 signaling pathway.7 Th17 cytokines can be produced by CD4+ T, CD8+ T, γδ T, natural killer T (NKT) and NK cells and can regulate effector functions of other immune cells after Mtb infection.8 Cellular signal pathways of Th17-related cytokines may be key modulators of adaptive immune responses.9 Th17-related cytokines can also trigger the production of anti-microbial peptides involved in the defense against bacterial pathogens.9

In this article, we review Th17-related cytokines, networks/signals and their roles in immune responses or immunity against Mtb infection. We also outline studies showing how Mtb microorganisms manipulate Th17-related cytokine pathways and upstream cytokines of the STAT3 signal in primary TB. Furthermore, we discuss the evidence that immune responses of the STAT3 signal pathway and Th17-like T-cell subsets are dysregulated or destroyed in patients with TB. Finally, we discuss future studies in TB research.

Th17-Related cytokines/Th17-like cells and their roles in Mtb infection

IL-17 and Th17 cells

IL-17 family cytokines contain six members, IL-17A–17F. Among them, IL-17A and IL-17F share a similar structure and have similar roles in the immune response against Mtb infection.10, 11 The roles of other members of the IL-17 family are currently not known in Mtb infection.

In patients with chronic TB, IL-17A production appears to be decreased. The production of IL-17A by peripheral blood mononuclear cells (PBMCs) isolated from chronic TB patients is significantly lower than PBMCs isolated from healthy control (HC) subjects. Under the ex vivo purified protein derivative stimulation, PBMCs from TB patients also secrete lower levels of IL-17A than those isolated from HC subjects. The decrease in IL-17A production, correlated with the exhaustion of T cells, may be due to the overexposure to Mtb antigens and hyperexpression of the exhausted marker programmed death-1 (PD-1).12, 13 Increased PD-1 expression appears to be relevant to the depressed production of IL-17A in TB because anti-PD-1 antibodies can enhance IL-17A production by Mtb-stimulated CD4+ T cells of TB patients.14 Anti-TB therapy can decrease PD-1 expression and increase IL-17A production by CD4+ T cells.15, 16

IL-17A is a protective cytokine against mycobacteria infection in the host; suppressing IL-17A production will increase TB susceptibility.17 In fact, there is a decreased risk for TB development related to the IL-17A–197A allele, AA genotype and A carrier (AG/AA).18 IL-17A is involved in the formation and stability of granulomas by increasing chemokine production, which helps recruit inflammatory cells migrating to the Mtb-infected sites.10, 19 The immune recall response of CD4+ T cells producing IL-17 occurs simultaneously with the expression of the chemokines of CXCL11, CXCL10 and CXCL9 and facilitates pulmonary recruitment of Th1 cells and anti-TB immunity.20 Virtually, IL-17RA, the A subset of the IL-17A receptor, can mediate the expression of CXCL-1 and CXCL-5, which are important for recruiting neutrophils moving to the lungs of Mtb-infected mice.21 Notably, when the IL-17A gene is knocked out in mice, granulomas in the mycobacteria-infected lung fail to mature, and the expression of adhesion molecules of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 decreases, which leads to an impaired protective response.19 Furthermore, the adoptive transfer of γδ T cells, which are the dominating IL-17A-producing cells in the lung granuloma, can rebuild granuloma in the IL-17A knockout (KO) mice.19

The immune protective role of IL-17F in Mtb infection is similar to IL-17A, which is 50% homologous to IL-17F in structure.17 The sequence variant of IL-17F is also correlated with susceptibility to TB.22 Interestingly, we have recently demonstrated that IL-17F and IL-17A can induce the recall response and effector function of TB phosphoantigen-specific Vγ2Vδ2 T cells after Bacillus Calmette–Guérin (BCG) immunization and Mtb infection in nonhuman primates,23 suggesting a role of IL-17 in adaptive γδ T-cell responses.

Interleukin-21

Th17/22-like γδ T cells, which express the transcription factor RORγt (retinoic acid receptor-related orphan receptor-γt) and IL-23R (IL-23 receptor), produce not only IL-17 and IL-22 but also IL-21 under the stimulation of IL-1β and IL-23; participation of the T-cell receptor is not necessary.7 After stimulation with Mtb antigens, NKT cells isolated from TB patients also produced IL-21 and other cytokines such as IL-17, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and IL-2.24, 25 IL-21-expressing NKT cells showed an effector memory phenotype and expressed CXCR5.25 However, the main sources producing IL-21 are activated CD4+ T cells with the induction of Mtb-specific peptides.26 IL-21 signaling plays important roles in host resistance to Mtb infection.27 In TB patients, circulating levels of IL-21 are significantly diminished compared with latent tuberculosis infection (LTBI) or HC individuals.27, 28

The IL-21/ IL-21R signaling pathway has pleiotropic effects on immunity and has an important role in T-cell immune responses against Mtb infection because it contributes to augment CD8+ T-cell priming and improve T-cell accumulation in the lungs, enhancing the production of effector cytokines.27 IL-21 signaling may also inhibit exhaustion of T cells since more CD4+ and CD8+ T cells expressing T-cell immunoglobulin and mucin domain 3 (TIM-3) and PD-1 are observed in chronically infected IL-21R−/− mice.12 These IL-21R KO mice show an increased susceptibility to Mtb infection, characterized by earlier mortality and higher lung bacterial burden compared with wild-type (WT) mice.27

Circulating T follicular helper (Tfh) cells can also produce IL-21 and have important roles in immunity to infections.29 The frequencies of Tfh cell subsets induced by Mtb antigen are significantly lower in TB patients than those in LTBI subjects.30 Similarly, frequencies of antigen-induced IL-21-producing Tfh cells are also obviously lower in TB patients, with diminished circulating levels of IL-21.30 Although IL-21 is associated with the expansion of B cells and helps B cells secrete antibodies of immunoglobulin G (IgG) and IgA, it may also participate in local immune responses for fighting against Mtb infection.25

IL-22 and Th22 cells

T cells and NK cells are the major sources of IL-22. Accumulating data suggest that Th17 and Th22 are two distinct cell subsets in humans and nonhuman primates.31 In TB patients, the IL-22 concentration in the serum is lower than that in LTBI subjects, and anti-TB treatment could enhance IL-22 antigen-specific responses in active TB patients.32, 33, 34 Although frequencies of Th22 cells in the blood of TB patients are low, the IL-22 protein level in bronchoalveolar lavage (BAL) fluid is high.35

IL-22 induces the production of anti-bacterial peptides including β-defensins, lipocalin and regenerating islet-3-γ from lung epithelial cells and monocytes and macrophages to kill pathogens.36 In addition, macrophages express the IL-22 receptor within TB granulomas in the lungs, and IL-22 can activate macrophages to mediate mycobacterial control and induce TNF-α production (refs 31, 37, 38, data not shown).

Surprisingly, the productions of IL-22 and IFN-γ are reciprocally related. The expression of IL-22 is significantly increased in the shortage of IFN-γ likewise, the production of IFN-γ is enhanced when monoclonal anti-IL-22 antibodies inhibit IL-22 signaling.39 For example, Vγ2Vδ2 T cells activated by phosphoantigen HMBPP ((E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate) can increase IFN-γ production and downregulate a potential over-reactive IL-22 response in lymphocytes from BAL fluid, blood and lymph nodes.31 The production of endogenous IFN-γ by HMBPP-activated Vγ2Vδ2 T cells appears to be the underlying mechanism since adding anti-IFN-γ-neutralizing antibody can abrogate or reduce the capability of HMBPP-induced Vγ2Vδ2 T cells to decrease IL-22 production.40, 41 Similarly, anti-IL-22 monoclonal antibody treatment can increase the expression of IFN-γ.39, 42 IL-22-producing cells may regulate protection against Mtb infection. Primary Mtb infection in nonhuman primates induces significant increases in T cells, producing IL-22. Moreover, these IL-22-producing cells are more apparent in the lungs than in the lymphoid tissues and blood.31, 40, 43 With the help of confocal microscopy and immunohistochemistry, IL-22-producing T cells can be detected in situ in lung TB granulomas.44 Appreciable numbers of mature IL-22-producing T cells in lung TB granulomas suggest that they may have an important role in protective immune responses to Mtb infection, despite the fact that an over-reactive IL-22 or Th22 response may also contribute to TB pathology.31 The hypothesis of protective IL-22/Th22 responses in TB is also supported by the observation that Th22 cells carrying membrane-borne IL-22 and IL-22 released by NK cells from Mtb-infected individuals can inhibit the intracellular growth of Mtb bacilli.38, 40

Moreover, the rs2227473 single-nucleotide polymorphism (SNP) in IL-22 is related to the risk of pulmonary TB, and the G allele is the risk factor.45 This SNP may have a significant role in the protective immune process against TB by affecting the IL-22 expression of PBMCs.45

Despite a lack of conclusive in vivo evidence,46 the above findings suggest that Th22 or IL-22 may contribute to protection against Mtb infection.38, 40, 42 Currently, functions and dysfunctions of IL-22 and Th22 cells in human TB remain incompletely characterized. Further in-depth studies may help elucidate the roles of IL-22/Th22 in anti-TB immunity or TB pathology.

Interleukin-23

IL-23 is a heterodimeric cytokine comprised of an IL-12B (IL-12p40) subunit and the IL-23A (IL-23p19) subunit, and its functional receptor includes IL-12Rβ1 and IL-23R. IL-23 is mainly produced by antigen-presenting cells.20 In vitro, Mtb can induce monocyte-derived dendritic cells (DCs) and human alveolar macrophages to produce IL-23.47, 48, 49 In vivo, the expression of IL-23α is enhanced in PBMCs in nonhuman primates at the early stage of mycobacteria infection; later, its expression decreases to the normal level.50 Moreover, levels of IL-12p40, one subunit of IL-23, are higher in the serum of TB patients than in HCs and decrease after anti-TB treatments.48, 50

IL-23 could mediate its effects on both innate and adaptive arms of the immune system that express the IL-23R.48 Th17 cells are the representative T-cell subset that vigorously responds to IL-23.51 The IL-23/IL-17 axis appears to act as an important modulator of immune responses associated with all phases of Mtb infection, with protective roles reported in a mouse TB model.20

TCR γδ T cells can be one of the main sources of IL-17 responding to IL-23 stimulation.52 Our studies recently showed that IL-23 and other Th17-related cytokines can induce proliferation and expansion of Vγ2Vδ2 T cells in the presence of HMBPP.23 Mycobacteria vaccination/infection of macaques enhances the ability of IL-23 to expand HMBPP-activated Vγ2Vδ2 T cells, and those expanded cells have multieffector functions for producing cytokines of IL-17, IL-22, IL-2 and IFN-γ.23 Autocrine production of IFN-γ and IL-2 can, in turn, enhance IL-23/HMBPP-stimulated recall-like expansion of Vγ2Vδ2 T cells.23, 53 The STAT3-dependent signal pathway is involved in the IL-23 expansion of Vγ2Vδ2 T cells.48, 54, 55 Data from studies using PBMCs of TB patients show that the IL-23-IL-17 axis is likely dysregulated or damaged by overexposure to stimulation of Mtb antigens in chronic infection.56, 57 This will be discussed in detail below.

In summary, these findings demonstrate that Th17-related cytokines and Th17/Th22 cells may be devoted to immune responses to Mtb infection and may be involved in protective immunity against primary Mtb infection. There are some experimental data implicating dysregulated immune responses of selected Th17-related cytokines in patients with TB.

Mtb microorganisms may manipulate Th17-related cytokine signaling pathways for their surviving benefits in primary Tb

In the primary Mtb infection phase, STAT3 pathways are stimulated in phagocytes (monocytes/macrophages),58 but their protective effects are suppressed by the products of Mtb and/or by immunosuppressive cytokines from Mtb-stimulated host cells.59, 60, 61 The STAT3 pathway and Th17-related cytokines appear to be influenced by Mtb infection in the following complex aspects.

After infection, virulent Mtb organisms survive in phagocytes, and Mtb antigens directly simulate the STAT3 signal pathway to regulate host immunity. The early secreted antigenic target of 6  kDa (ESAT-6) is an essential virulence factor, stimulating macrophages to produce IL-6 via STAT3 activation (Figure 1).62 It induces phosphorylation and DNA binding of STAT3, which can be blocked by STAT3 inhibitors.62 The induced IL-6 is responsible for the suppression of Th1 responses and the suppression of Mtb-infected and Mtb-uninfected bystander macrophage responses to IFN-γ, which induces autophagy in Mtb-infected macrophages.63, 64 Mtb antigens expressed in latency, such as α-crystalline 1 (Acr1), can also interfere with the differentiation of DCs by targeting STAT3 pathways (Figure 1).65 Continuous activation of STAT3 would inhibit the translocation of nuclear factor-κB (NF-κB) in DCs treated by Acr1.65 Thus, Mtb in latently infected individuals could use these strategies to survive and antagonize the attempts of eradication by the anti-TB immune system.

Figure 1.

Figure 1

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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 phosphorylation 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 nitric oxide 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.

Mtb infection induces the production of immunosuppressive cytokines including IL-10 to affect STAT3 activation.66 After Mtb infection, IL-10 levels and STAT3 and pSTAT3 expression levels increase significantly in the first week. The production of IL-10 is strongly correlated with the expression of STAT3 and pSTAT3 proteins.67 In vitro, IL-10 can regulate the protective phenotype in Mtb-infected phagocytes including monocyte-derived macrophages, phorbol myristate acetate-treated THP-1 cells and human alveolar macrophages.68 IL-10 plays its immunosuppressive effects on this early response of Mtb-infected macrophages in a partly STAT3-dependent manner. The inhibitory activity of Mtb would be reversed when IL-10 is neutralized through the addition of soluble IL-10 receptor.66 The interaction of Mtb with differentiating monocytes rapidly activates the STAT pathway, which likely participates in IL-10 gene expression.69 STAT3 activation leads to the inhibition of cytokines IL-6, IFN-γ, TNF-α and MIP-1β (macrophage inflammatory protein-1β).70 In the primary infection phase, STAT3 also represses the expression/synthesis of inducible nitric oxide synthase and nitric oxide, which are important factors that kill intracellular Mtb.2, 71

Unlike virulent Mtb, the TB vaccine BCG can drive effective Th1-cell responses dependent on Th17-related cytokines to defeat IL-10 inhibitory effects induced by bacteria. Prostaglandin-E2 induced by BCG promotes IL-10 expression while simultaneously inducing IL-23 production and differentiation of Th17 cells. The ability of IL-17 to decrease IL-10 and increase IL-12 production admits the generation of protective Th1-cell responses and subsequent vaccine-induced protection against Mtb challenge. Thus, the IL-23/IL-17 pathway could overcome IL-10-mediated inhibition to drive Th1-cell responses.51

IL-27, another immunosuppressive cytokine, can also modulate the STAT3 pathway.72 In vitro, IL-27 induces STAT3 phosphorylation and inhibits activated macrophages to produce TNF-α and IL-12 and regulate the Th1 response during Mtb infection.72 Furthermore, IL-27 can modulate excessive inflammation via a feedback mechanism.72, 73 Whether this can be observed in vivo remains to be investigated in TB.

Mtb infection may manipulate or utilize the STAT3 pathway by inducing the differentiation of monocytes toward an immunosuppressive (M2-like) macrophage activation program.70 These M2-like macrophages are characterized by the phenotype of CD16+CD163+MerTK+pSTAT3+ and can function as an immunomodulator.67 This process relies on STAT3 activation and shows a detrimental role in TB.67 There is a significant connection between the progression of the disease and the copiousness of the CD16+CD163+MerTK+pSTAT3+ cells.67

Mtb infection could also regulate the STAT3 effect by mediating the expression of microRNAs (miRNAs) targeted on STAT3.55, 74 Mtb infection causes the downregulation of miR-17 and corresponding upregulation of its target STAT3 to suppress autophagy,74, 75 which has an important role in the bacterial burden control.76 Forced expression of miR-17 reduces the production of STAT3 and regulates autophagy.74

Thus, in vitro or animal studies demonstrate that during primary TB, Mtb microorganisms can manipulate the STAT3 pathway for their surviving benefits using the following strategies: producing Mtb products, inducing immunosuppressive cytokine/inflammatory macrophage induction and altering specific miRNAs targeting STAT3.

Immune responses of the STAT3 pathway and Th17-like cells are dysregulated or destroyed in Tb patients

In TB patients, the chronic Mtb infection appears to destroy the STAT3 signal pathway in T cells, leading to selective impairing of the signal effect of IL-23.53, 59 IL-23 is a positive regulator of the STAT3 signal pathway and can act on both the differentiation of CD4 Th0 to IL-23R-expressing Th17 cells and the maturation of γδ T cells, which constitutively express IL-23R and are important sources to produce IL-17.20

CD4 T cells of TB patients are demonstrated to secrete less IL-17 under stimulation of Mtb than do those of LTBI subjects,48 although Mtb-stimulated monocytes from TB patients express similar amounts of IL-23p19 mRNA and protein as those from LTBI subjects. Mtb-stimulated CD4+ T cells from TB patients express less IL-23R and pSTAT3 than those from LTBI subjects.16 This may be correlated with highly expressed PD-1 because a blockade by anti-PD-1 antibodies can enhance IL-23R and pSTAT3 expression and IL-17 production by Mtb-stimulated CD4+ T cells from TB patients.77 Anti-TB therapy can decrease PD-1 expression and increase the expression of IL-17, IFN-γ, pSTAT3 and IL-23R. Chronic TB may depress the STAT3 signal pathway, leading to a decrease in the expression of IL-23R and production of IL-17 by CD4+ T cells in TB patients (Figure 2).

Figure 2.

Figure 2

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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, T helper 17.

Interestingly, our recent studies in humans have shown that TB patients exhibit selective impairing of the IL-23 signal effect on the TB phosphoantigen HMBPP-specific γδ T-cell subset, with a consequence of IL-23-targeted exhaustion of Vγ2Vδ2 T-cell responses.53, 78, 79 Such selective impairing of the IL-23 signaling effect can be linked to depressed expression and phosphorylation of STAT3 and the overexpression of antagonizing factor SOCS3.60, 61 The downregulation of the STAT3 signal pathway in Vγ2Vδ2 T cells correlates with remarkable increases in two miRNAs targeting STAT3 (Figure 2). hsa-miR-337-3p and hsa-miRNA-125b-5p are expressed much higher in Vγ2Vδ2 T cells from TB patients compared with those from HC subjects with a BCG vaccination history (Figure 2). Most strikingly, the downregulation of hsa-miR-337-3p and hsa-miRNA-125b-5p using an miRNA sponge allows for detectable recovery of IL-23-induced expansion of Vγ2Vδ2 T cells in TB patients and their effector functions for producing anti-TB cytokines of IFN-γ and IL-17A.53

By contrast, the IL-2 signaling pathway does not appear to be disrupted in TB because IL-2+HMBPP still can expand Vγ2Vδ2 T cells in peripheral blood from TB patients.53, 80 Although IL-2 synergizes or facilitates the IL-23-induced expansion of Vγ2Vδ2 T cells, the IL-2 blockade cannot completely abrogate the IL-23-induced expansion.53 This notion is also supported by the STAT3 blockade data demonstrating that STAT3 has an important role in the expansion of Vγ2Vδ2 T cells by IL-23, but not IL-2.80, 81, 82 It is interesting to demonstrate that TB can selectively impair IL-23 signaling but spare IL-2 effects on Vγ2Vδ2 T cells.53, 80 Such selective impairing of the IL-23 effect may occur as a result of persistent exposure of Vγ2Vδ2 T cells to phosphoantigen HMBPP or IL-23 during chronic TB infection.

Unlike CD4+ T cells, TB-driven impairing of the IL-23-induced expansion of HMBPP-specific Vγ2Vδ2 T cells cannot be explained by T-cell exhaustion linked to PD-1 signaling. Although Ab blocking of the PD-1 pathway can reverse the exhaustion of αβ T cells linked to PD-1 expression,83 this blockade cannot restore IL-23 induced expansion of Vγ2Vδ2 T cells despite our use of two different sources of PD-1 Abs capable of recovering from T-cell exhaustion.

Mtb infection regulates the expression of upstream cytokines in the STAT3 pathway, driving Th17-like responses

Cytokines of TGF-β, IL-6 and IL-1β are regulatory mediators upstream of the STAT3 pathway. These upstream cytokines have been shown to undergo significant changes in Mtb infection, although it is unknown how each contributes to dysregulation of Th17-like responses in TB. Below are the reported changes in these cytokines in Mtb infection, mostly in patients with TB.

Transforming growth factor-β

TGF-β belongs to the TGF superfamily produced by all white blood cell lineages.84 Costimulation of TGF-β with IL-6 is required for Th17 cell differentiation.85 The TGF-β1 content in the serum of TB patients is higher than that in HC controls, and the serum level of TGF-β1 is directly related to the bacterial load and radiological severity.86 Moreover, PBMCs from TB patients produce more TGF-β than those from LTBI under Mtb antigen stimulation. The overexpression of TGF-β in TB patients appears to be transient, and the values return to normal ranges at the end of 3 months of treatment in sequential studies. Although TGF-β can act as an anti-inflammatory cytokine, the immunological significance of changes in this cytokine of TB patients remains to be investigated.

Interleukin-6

IL-6 could initiate early proinflammatory responses, such as to induce the differentiation of T cells producing IL-17. Compared with HC subjects, TB patients have higher baseline levels of serum IL-6.87 Four months after anti-TB drug treatment, IL-6 levels rapidly decrease and stabilize in TB patients. These results indicate that IL-6 may participate in the regulation of immune responses to Mtb infection.87

Interleukin-1β

IL-1β is part of an 11-member IL-1 cytokine family and signals through IL-1R.88 IL-1β is mainly produced by monocytes and DCs and is vital to the Th17 response to Mtb.88 IL-1β functions as the innate Th17-polarizing cytokine and determines the outcome of the Th17 response to Mtb and its antigen fractions.89 The amounts of secreted IL-1β are significantly correlated with Th17 responses,90 and exogenous replenishment of IL-1β is sufficient to markedly increase the Th17 response by the Mtb cytoplasmic fraction.89 Moreover, the receptor of IL-1β and IL-18 receptor engagement induce an Mtb antigen-specific Th1/Th17 immune response.91, 92

Notably, although these upstream cytokines of the STAT3 pathway are highly expressed in TB patients, STAT3-driven immune responses of Th17 cells and dominant Ag-specific Vγ2Vδ2 T-cell subsets are dysregulated or impaired. This may be attributed to the dysfunction or destruction of the STAT3 pathway, which is characterized by decreases in expression and phosphorylation of STAT3 and marked increases of microRNAs that downregulate STAT3, leading to no or a reduced response to IL-23 or Th17-related cytokines.

Th17-related cytokines in Tb pathology

TB pathogenesis is critically related to the extent of inflammation.93 Therefore, Th17 responses in TB are presumed to participate in pathology according to their activities, such as neutrophil recruitment and promoting inflammatory responses in infection sites,93, 94 which will cause serious tissue damage in redundancy neutrophils and high degrees of inflammation.93 Recently, it was reported that there are more IL-17-producing T cells and IL-2- and IL-10-producing T cells in the lung granulomas of latent Mtb-infected macaques with a high risk of reactivation than those in low-risk animals identified by positron emission tomography CT.95 Therefore, high lung inflammation is associated with TB reactivation from LTBI.

Moreover, IL-22 is also suggested to participate in inducing TB pathology.96 IL-22 was readily identified in disease sites of pericardial and pleural effusions of human TB, and the levels of IL-22 are associated with the levels of matrix metalloproteinase-9, which degrades the extracellular matrix components, causing pathology.96 Because TB is a complex disease, cytokine-induced protective or pathological consequences are critically related to the balance of hemostasis. Based on the present data, the roles of Th17-related cytokines cannot be simply defined as ‘good’ or ‘bad’. Further detailed study is necessary to describe the features of the development of these cytokines in local disease sites and define their roles in TB pathology or protection.

Future studies and perspectives

It is important to note that most of the above observations describing dysregulated responses of Th17-related cytokines, STAT3 and Th17-like cells are made in the setting of primary Mtb infection or the utilization of blood samples from TB patients. This raises a critical question as to whether those findings can indeed closely represent immune responses or immunopathogenesis occurring in the pulmonary compartment or lung tissue of TB patients. This is not a trivial question because TB is a chronic, complex disease that is accompanied by pathological processes in the lung tissue. More investigations in the lung and pulmonary compartment of TB patients will display many aspects distinct from what is observed in the blood. In fact, there are compelling lines of evidence that Th17-related cytokines and Th17-like cells are remarkably different from those observed in the blood in TB.31, 97 Thus, in-depth studies using pulmonary compartment samples from TB patients are necessary. It would also be useful to conduct mechanistic studies of TB immunology/pathobiology in lungs using an improved nonhuman primate TB model mimicking chronic TB in humans.

Th17-related cytokines could contribute to immune protection against primary Mtb infection, and their expression levels are decreased in TB patients. Such decreases may be related to the exhaustion of T cells as a result of prolonged overexposure to the stimulation of Mtb antigens in chronic infection. The production of Th17-related cytokines is dependent on the STAT3 signal pathway, and this pathway is dysregulated or damaged in TB infection, with decreases in the expression and phosphorylation of STAT3 and marked increases in microRNAs targeting STAT3. Such dysregulated or deficient conditions may provide a rationale for adjunctive replacement treatment targeting Th17 responses. This notion is supported by recent reports demonstrating that treatments with IL-2 and others can result in beneficial results for attenuating chronic non-tuberculosis mycobacteria (NTM) pulmonary disease.98, 99, 100, 101

Conversely, the overproduction of Th17-related cytokines in TB patients may be detrimental and contribute to TB pathology. If advanced studies confirm that IL-22 or other related cytokines have an active role in TB pathology in the lungs, immune interventions controlling for the overproduction of IL-22 or others may be explored as a potential adjunctive host-directed therapy.13, 42, 91, 96

Acknowledgments

This work was supported by the following research grants: The National Key Research and Development Program of China (2016YFA0502204); the National Institutes of Health R01 grants (NIH R01 HL64560/OD015092/HL129887 to ZWC).

Footnotes

The authors declare no conflict of interest.

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