Cellular and Molecular Immunology (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 cytokines/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 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. 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 immune system 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 interleukin- lives in macrophages and lung 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 growth factor-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 cell signaling 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 217 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 transcription factor IL-17 family cytokines contain six members, IL-17A–17F. RORγt (retinoic acid receptor-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, interferon-γ be decreased. The production of IL-17A by peripheral blood (IFN-γ), tumor necrosis factor-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 protein 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 lungs, 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 chemokine 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 chemokines 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 neutrophils 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 gene 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.