IL‐6: Regulator of Treg/Th17 balance

IL‐6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL‐6 has a very important role in regulating the balance between IL‐17‐producing Th17 cells and regulatory T cells (Treg). The two T‐cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T‐cell responses. IL‐6 induces the development of Th17 cells from naïve T cells together with TGF‐β; in contrast, IL‐6 inhibits TGF‐β‐induced Treg differentiation. Dysregulation or overproduction of IL‐6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology. Given the critical role of IL‐6 in altering the balance between Treg and Th17 cells, controlling IL‐6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases. Here, we review the role of IL‐6 in regulating Th17/Treg balance and describe the critical functions of IL‐6 and Th17 in immunity and immune‐pathology.     

In vitro‐induced Th17 cells fail to induce inflammation in vivo and show an impaired migration into inflamed sites

Recently, IL‐17 produced by Th17 cells was described as pro‐inflammatory cytokine with an eminent role in autoimmune diseases, e.g. rheumatoid arthritis. A lack of IL‐17 leads to amelioration of collagen‐induced arthritis. IL‐17 induction in naïve CD4⁺ T cells depends on IL‐6 and TGF‐β and is enhanced by IL‐23. The in vivo inflammatory potential of in vitro‐primed Th17 cells however, remains unclear. Here, we show that, although IL‐17 neutralisation results in amelioration of murine OVA‐induced arthritis, in vitro‐primed Th17 cells cannot exacerbate arthritic symptoms after adoptive transfer. Furthermore, Th17 cells cannot induce an inflammatory delayed type hypersensitivity reaction because they fail to migrate into inflamed sites, possibly due to the lack of CXCR3 expression. Also, re‐isolated Th17 cells acquired IFN‐γ expression, indicating instability of the Th17 phenotype. Taken together, the data show that IL‐6, TGF‐β and IL‐23 might not provide sufficient signals to induce “fully qualified” Th17 cells.     

Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells

Leptin is an adipose‐secreted hormone that plays an important role in both metabolism and immunity. Leptin has been shown to induce Th1‐cell polarization and inhibit Th2‐cell responses. Additionally, leptin induces Th17‐cell responses, inhibits regulatory T (Treg) cells and modulates autoimmune diseases. Here, we investigated whether leptin mediates its activity on T cells by influencing dendritic cells (DCs) to promote Th17 and Treg‐cell immune responses in mice. We observed that leptin deficiency (i) reduced the expression of DC maturation markers, (ii) decreased DC production of IL‐12, TNF‐α, and IL‐6, (iii) increased DC production of TGF‐β, and (iv) limited the capacity of DCs to induce syngeneic CD4⁺ T‐cell proliferation. As a consequence of this unique phenotype, DCs generated under leptin‐free conditions induced Treg or T_H17 cells more efficiently than DCs generated in the presence of leptin. These data indicate important roles for leptin in DC homeostasis and the initiation and maintenance of inflammatory and regulatory immune responses by DCs.     

Interleukin‐6 blockade in ocular inflammatory diseases

Interleukin‐6 (IL‐6) is a key cytokine featuring redundancy and pleiotropic activity. It plays a central role in host defence against environmental stress such as infection and injury. Dysregulated, persistent interleukin (IL)‐6 production has been implicated in the development of various autoimmune, chronic inflammatory diseases and even cancers. Significant elevation of IL‐6 has been found in ocular fluids derived from refractory/chronic uveitis patients. In experimental autoimmune uveitis models with IL‐6 knock‐out mice, IL‐6 has shown to be essential for inducing inflammation. IL‐6 blockade can suppress acute T helper type 17 (Th17) responses via its differentiation and, importantly, can ameliorate chronic inflammation. Tocilizumab, a recombinant humanized anti‐IL‐6 receptor antibody, has been shown to be effective in several autoimmune diseases, including uveitis. Herein, we discuss the basic biology of IL‐6 and its role in development of autoimmune conditions, focusing particularly on non‐infectious uveitis. It also provides an overview of efficacy and safety of tocilizumab therapy for ocular inflammatory diseases.     

A novel IL‐23p19/Ebi3 (IL‐39) cytokine mediates inflammation in Lupus‐like mice

Interleukin‐12 family cytokines have emerged as critical regulators of immunity with some members (IL‐12, IL‐23) associated with disease pathogenesis while others (IL‐27, IL‐35) mitigate autoimmune diseases. Each IL‐12 family member is comprised of an α and a β chain, and chain‐sharing is a key feature. Although four bona fide members have thus far been described, promiscuous chain‐pairing between alpha (IL‐23p19, IL‐27p28, IL‐12/IL‐35p35) and beta (IL‐12/IL‐23p40, IL‐27/IL‐35Ebi3) subunits, predicts six possible heterodimeric IL‐12 family cytokines. Here, we describe a new IL‐12 member composed of IL‐23p19 and Ebi3 heterodimer (IL‐39) that is secreted by LPS‐stimulated B cells and GL7⁺ activated B cells of lupus‐like mice. We further show that IL‐39 mediates inflammatory responses through activation of STAT1/STAT3 in lupus‐like mice. Taken together, our results show that IL‐39 might contribute to immunopathogenic mechanisms of systemic lupus erythematosus, and could be used as a possible target for its treatment.     

Cytokines that regulate autoimmunity

Recent advances have revealed new insights in cytokine regulation of inflammatory responses. TGFbeta acting together with pro-inflammatory cytokines such as IL-6 promotes lineage commitment of RORgamma-dependent Th17 cells. IL-23--a member of the IL-12 family--activates the effector function of Th17 cells to promote skin, lung, and mucosal immunity. However, when dysregulated, these cells are important players in autoimmune inflammation. Unexpectedly, IL-27--another IL-12 family member--plays an opposing role by inducing IL-10 production as well as downregulating both Th17 and Th1-mediated immune pathologies.     

IL‐12‐polarized Th1 cells produce GM‐CSF and induce EAE independent of IL‐23

CD4⁺ T‐helper (Th) cells reactive against myelin antigens mediate the mouse model experimental autoimmune encephalomyelitis (EAE) and have been implicated in the pathogenesis of multiple sclerosis (MS). It is currently debated whether encephalitogenic Th cells are heterogeneous or arise from a single lineage. In the current study, we challenge the dogma that stimulation with the monokine IL‐23 is universally required for the acquisition of pathogenic properties by myelin‐reactive T cells. We show that IL‐12‐modulated Th1 cells readily produce IFN‐γ and GM‐CSF in the CNS of mice and induce a severe form of EAE via an IL‐23‐independent pathway. Th1‐mediated EAE is characterized by monocyte‐rich CNS infiltrates, elicits a strong proinflammatory cytokine response in the CNS, and is partially CCR2 dependent. Conversely, IL‐23‐modulated, stable Th17 cells induce EAE with a relatively mild course via an IL‐12‐independent pathway. These data provide definitive evidence that autoimmune disease can be driven by distinct CD4⁺ T‐helper‐cell subsets and polarizing factors.     

Induction, function and regulation of IL-17-producing T cells

Recent reports have provided convincing evidence that IL‐17‐producing T cells play a key role in the pathogenesis of organ‐specific autoimmune diseases, a function previously attributed exclusively to IFN‐γ‐secreting Th1 cells. Furthermore, it appears that IL‐17‐producing T cells can also function with Th1 cells to mediate protective immunity to pathogens. Although much of the focus has been on IL‐17‐secreting CD4⁺ T cells, termed Th17 cells, CD8⁺ T cells, γδ T cells and NKT cells are also capable of secreting IL‐17. The differentiation of Th17 cells from naïve T cells appears to involve signals from TGF‐β, IL‐6, IL‐21, IL‐1β and IL‐23. Furthermore, IL‐1α or IL‐1β in synergy with IL‐23 can promote IL‐17 secretion from memory T cells. The induction or function of Th17 cells is regulated by cytokines secreted by the other major subtypes of T cells, including IFN‐γ, IL‐4, IL‐10 and at high concentrations, TGF‐β. The main function of IL‐17‐secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF‐α, IL‐1β and IL‐6, and inflammatory chemokines that promote the recruitment of neutrophils and macrophages.     

Chloroquine‐treated dendritic cells require STAT1 signaling for their tolerogenic activity

MS and EAE are T cell‐driven autoimmune diseases of the CNS where IL‐17‐producing Th17 cells promote damage and are pathogenic. Conversely, tolerogenic DCs induce Treg cells and suppress Th17 cells. Chloroquine (CQ) suppresses EAE through the modulation of DCs by unknown mechanisms. Here, we show that STAT 1 is necessary for CQ‐induced tolerogenic DCs (tolDCs) to efficiently suppress EAE. We observed that CQ induces phosphorylation of STAT1 in DCs in vivo and in vitro. Genetic blockage of STAT1 abrogated the suppressive activity of CQ‐treated DCs. Opposed to its WT counterparts, CQ‐treated STAT1^?/? BMDCs were unable to suppress Th17 cells and increased EAE severity. Our findings show that STAT1 is a major signaling pathway in CQ‐induced tolDCs and may shed light on new therapeutic avenues for the induction of tolDCs in autoimmune diseases such as MS.     

Human TSLP and TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under Th2-polarizing conditions

Background Human thymic stromal lymphopoietin (TSLP) is expressed in the human asthmatic lung and activates dendritic cells (DCs) to strongly induce proallergic T‐helper type 2 (Th2) cell responses, suggesting that TSLP plays a critical role in the pathophysiology of human asthma. Th2 cells are predominantly involved in mild asthma, whereas a mixture of Th1 and Th2 cells with neutrophilic inflammation, probably induced by Th17, affects more severe asthmatic disease. Exacerbation of asthmatic inflammation is often triggered by airway‐targeting RNA viral infection; virus‐derived double‐stranded RNA, Toll‐like receptor (TLR)3 ligand, activates bronchial epithelial cells to produce pro‐inflammatory mediators, including TSLP. Objective Because TSLPR‐expressing DCs express TLR3, we examined how the relationship between TSLP and TLR3 ligand stimulation influences DC activation. Methods CD11c⁺DCs purified from adult peripheral blood were cultured in TLR ligands containing media with or without TSLP and then co‐cultured with allogeneic naïve CD4⁺T cells. Results CD11c⁺ DCs responded to a combination of TSLP and TLR3 ligand, poly(I : C), to up‐regulate expression of the functional TSLP receptor and TLR3. Although TSLP alone did not induce IL‐23 production by DCs, poly(I : C) alone primed DCs for the production of IL‐23, and a combination of TSLP and poly(I : C) primed DCs for further production of IL‐23. The addition of poly(I : C) did not inhibit TSLP‐activated DCs to prime naïve CD4⁺ T cells to differentiate into inflammatory Th2 cells. Furthermore, DCs activated by a combination of TSLP and poly(I : C) primed more naïve CD4⁺ T cells to differentiate into Th17‐cytokine–producing cells with a central memory T cell phenotype compared with DCs activated by poly(I : C) alone. Conclusions These results suggest that through DC activation, human TSLP and TLR3 ligands promote differentiation of Th17 cells with the central memory T cell phenotype under Th2‐polarizing conditions.     

Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses

Allergic diseases are often triggered by environmental allergens that induce dominant type 2 immune responses, characterized by the infiltrated T‐helper type 2 (TH2) lymphocytes, eosinophils, and elevated TH2 cytokines. In addition to TH2 type immune responses, epithelial stress and injury linked to tissue remodelling are often observed, suggesting that epithelial cells may play important role in regulating allergic responses. Dendritic cells (DCs), the professional antigen‐presenting cells with the capabilities of sampling allergens, are considered as the key player on instructing TH2 immune responses. Whether inflamed epithelium can regulate innate immunity, such as macrophages and DCs, which in turn instructs adaptive immunity has long been hypothesized. Studies of thymic stromal lymphopoietin (TSLP), an epithelial cells‐derived cytokine, that can strongly activate DCs, provide important evidences that the epithelial barrier can trigger allergic diseases by regulating immune responses. The finding that OX40/OX40Ligand (OX40L) interactions are the molecular trigger responsible for the induction and maintenance of TH2 responses by TSLP‐activated DCs provides a plausible molecular explanation for TSLP‐mediated allergy. Recent progresses in characterizing the pro‐inflammatory IL‐17 cytokine family have added an additional layer of complexity on the regulation of allergic inflammation. TSLP–DCs can induce a robust expansion of TH2 memory cells and strengthen functional attributes by up‐regulating their surface expression of IL‐17RB (IL‐25R), the receptor for cytokine IL‐17E (IL‐25), a distinct member of IL‐17 cytokine family. IL‐17E (also known as IL‐25) produced by epithelial cells, and other innate cells, such as eosinphils, basophils, and mast cells, are shown to regulate adaptive immunity by enhancing TH2 cytokine productions. These exciting findings expand our knowledge of the complex immunological cascades that result in allergic inflammation and may provide novel therapeutic approaches for the treatment of allergic diseases.     

Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis

Interleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. It orchestrates innate and T cell-mediated inflammatory pathways and can promote T helper 17 (Th17) cell responses. Utilizing a T cell transfer model, we showed that IL-23-dependent colitis did not require IL-17 secretion by T cells. Furthermore, IL-23-independent intestinal inflammation could develop if immunosuppressive pathways were reduced. The frequency of naive T cell-derived Foxp3+ cells in the colon increased in the absence of IL-23, indicating a role for IL-23 in controlling regulatory T cell induction. Foxp3-deficient T cells induced colitis when transferred into recipients lacking IL-23p19, showing that IL-23 was not essential for intestinal inflammation in the absence of Foxp3. Taken together, our data indicate that overriding immunosuppressive pathways is an important function of IL-23 in the intestine and could influence not only Th17 cell activity but also other types of immune responses.     

Reduced TCR‐dependent activation through citrullination of a T‐cell epitope enhances Th17 development by disruption of the STAT3/5 balance

Citrullination is a post‐translational modification of arginine that commonly occurs in inflammatory tissues. Because T‐cell receptor (TCR) signal quantity and quality can regulate T‐cell differentiation, citrullination within a T‐cell epitope has potential implications for T‐cell effector function. Here, we investigated how citrullination of an immunedominant T‐cell epitope affected Th17 development. Murine naïve CD4⁺ T cells with a transgenic TCR recognising p89‐103 of the G1 domain of aggrecan (agg) were co‐cultured with syngeneic bone marrow‐derived dendritic cells (BMDC) presenting the native or citrullinated peptides. In the presence of pro‐Th17 cytokines, the peptide citrullinated on residue 93 (R93Cit) significantly enhanced Th17 development whilst impairing the Th2 response, compared to the native peptide. T cells responding to R93Cit produced less IL‐2, expressed lower levels of the IL‐2 receptor subunit CD25, and showed reduced STAT5 phosphorylation, whilst STAT3 activation was unaltered. IL‐2 blockade in native p89‐103‐primed T cells enhanced the phosphorylated STAT3/STAT5 ratio, and concomitantly enhanced Th17 development. Our data illustrate how a post‐translational modification of a TCR contact point may promote Th17 development by altering the balance between STAT5 and STAT3 activation in responding T cells, and provide new insight into how protein citrullination may influence effector Th‐cell development in inflammatory disorders.     

IL-13-producing Th1 and Th17 cells characterize adaptive responses to both self and foreign antigens

In helper T cells, IL‐13 is traditionally considered a Th2‐type cytokine that is coexpressed with IL‐4. Using mouse models of immunization and autoimmunity, we demonstrate that IL‐13 is frequently uncoupled from IL‐4, and that it can be produced by both IFN‐γ⁺ Th1 cells and IL‐17⁺ Th17 cells. We report that these IL‐13‐producing Th1 and Th17 cells are distinct from classical IL‐4⁺ Th2 cells and that they are relatively common, appearing in the context of both protective and pathogenic T‐cell responses. We also demonstrate that IL‐13 and Th2‐type cytokines can have important consequences in Th1‐ and Th17‐dominated settings, such as lymphopenia‐induced autoimmune disease, where they can be either pro‐ or anti‐inflammatory, depending on whether they act on innate or adaptive immune cells. Taken together, our studies indicate that IL‐13 production is more widespread than previously appreciated and that blocking this cytokine may have therapeutic benefits even in settings where traditional IL‐4‐driven Th2‐type responses are not evident.     

Interleukin-23: as a drug target for autoimmune inflammatory diseases

Interleukin-23 (IL-23) is a member of the IL-12 family of cytokines with pro-inflammatory properties. Its ability to potently enhance the expansion of T helper type 17 (Th17) cells indicates the responsibility for many of the inflammatory autoimmune responses. Emerging data demonstrate that IL-23 is a key participant in central regulation of the cellular mechanisms involved in inflammation. Both IL-23 and IL-17 form a new axis through Th17 cells, which has evolved in response to human diseases associated with immunoactivation and immunopathogeny, including bacterial or viral infections and chronic inflammation. Targeting of IL-23 or the IL-23 receptor or IL-23 axis is a potential therapeutic approach for autoimmune diseases including psoriasis, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. The current review focuses on the immunobiology of IL-23 and summarizes the most recent findings on the role of IL-23 in the pre-clinical and ongoing clinical studies.     

IL‐22 and inflammation: Leukin' through a glass onion

IL‐22 is a Th17 T‐cell‐associated cytokine that is highly expressed during chronic inflammation. IL‐22 receptor expression is absent on immune cells, but is instead restricted to the tissues, providing signaling directionality from the immune system to the tissues. Through Stat3 signaling, IL‐22 induces a variety of proliferative, anti‐apoptotic, and anti‐microbial pathways. IL‐22 is bi‐functional with both pro‐inflammatory and protective effects on tissues depending on the inflammatory context. The cytokine plays a role both in the host response against extracellular pathogens and in the inflammation associated with autoimmune diseases. Therapeutics targeting IL‐22 therefore may have promise for treating various chronic inflammatory diseases.