An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction

Zhu, Chen; Sakuishi, Kaori; Xiao, Sheng; Sun, Zhiyi; Zaghouani, Sarah; Gu, Guangxiang; Wang, Chao; Tan, Dewar J.; Wu, Chuan; Rangachari, Manu; Pertel, Thomas; Jin, Hyun-Tak; Ahmed, Rafi; Anderson, Ana C.; Kuchroo, Vijay K.

doi:10.1038/ncomms7072

Cited by 172 publications

(163 citation statements)

References 45 publications

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“…The promotion of Tim-3 expression in MS patients after IFN-β therapy is in line with a recent study showing that IL-27, which is potently induced by IFN-β, promotes not only Tim-3, but also IL-10 expression on murine T cells (Zhu et al, 2015). In addition, a recent study shows that IFN–β can induce Tim-3 directly on murine Th1 cells (Boivin et al, 2015).…”

Section: Tim-3supporting

confidence: 85%

“…Given that Tr1 cells also express Lag-3 (Gagliani et al, 2013), these observations raise the possibility that Tim-3, Lag-3, and potentially other co-inhibitory receptors have an important regulatory role in Tr1 cells and are in line with the demonstrated role of IL-27 in promoting resolution of autoimmune tissue inflammation (Fitzgerald et al, 2007a; Fitzgerald et al, 2007b) and suppressing anti-tumor immunity (Zhu et al, 2015). Thus, Tim-3 functions in both effector and regulatory T lymphocyte subsets to regulate immune responses at sites of tissue inflammation.…”

Section: Tim-3mentioning

confidence: 81%

“…IL-27, a heterodimeric immunosuppressive cytokine, is a potent inducer of Tr1 cells (Awasthi et al, 2007) and, as mentioned above, also drives the expression of Tim-3 on CD4 + T cells (Zhu et al, 2015). Given that Tr1 cells also express Lag-3 (Gagliani et al, 2013), these observations raise the possibility that Tim-3, Lag-3, and potentially other co-inhibitory receptors have an important regulatory role in Tr1 cells and are in line with the demonstrated role of IL-27 in promoting resolution of autoimmune tissue inflammation (Fitzgerald et al, 2007a; Fitzgerald et al, 2007b) and suppressing anti-tumor immunity (Zhu et al, 2015).…”

Section: Tim-3mentioning

confidence: 99%

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Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation

2016

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Summary Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T cell responses and have proven to be effective targets in the setting of chronic diseases where constitutive co-inhibitory receptor expression on T cells dampens effector T cell responses. Unfortunately, many patients still fail to respond to therapies that target CTLA-4 and PD-1. The next wave of co-inhibitory receptor targets that are being explored in clinical trials include Lag-3, Tim-3, and TIGIT. These receptors while belonging to the same class of receptors as PD-1 and CTLA-4 exhibit unique functions especially at tissue sites where they regulate distinct aspects of immunity. Increased understanding of the specialized functions of these receptors will inform the rational application of therapies that target these receptors to the clinic.

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Section: Tim-3supporting

confidence: 85%

Section: Tim-3mentioning

confidence: 81%

Section: Tim-3mentioning

confidence: 99%

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Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation

2016

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“…EBi3 can form heterodimeric cytokines when combined with IL-12p35, forming IL-35, or with IL-27p28, forming IL-27. The latter can regulate a variety of T cell-mediated immune responses, such as inhibition of Th2 (11) and Th17 development (12), induction of the regulatory molecule Tim3 in Th1 cells (13), and induction of IL-10 secretion by Th1 lymphocytes and CD8 ϩ T cells (14,15). The role of IL-27 in Leishmania infection is dependent on the species and/or experimental setting utilized.…”

mentioning

confidence: 99%

Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17–Neutrophil Response

et al. 2016

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bThe relationship established between Leishmania infantum and the vertebrate host can lead to a self-healing infection or to the manifestation of visceral leishmaniasis, a chronic systemic infection associated with high rates of mortality. We hypothesized that regulatory cytokines, such as interleukin-27 (IL-27), play a role in susceptibility to L. infantum infection. IL-27 is a heterodimeric cytokine composed of IL-27p28 and EBi3 subunits which, when combined, bind to IL-27R, leading to STAT-1 and -3 activation, playing a role in the regulation of the immune response. We observed in this work that IL-27 regulates the Th1/Th17 profiles in a mouse model of visceral leishmaniasis (VL) caused by L. infantum. We showed here that the pathogen recognition by endosomal Toll-like receptors triggers a type I interferon (IFN) response, which acts through the type I IFN receptor and interferon regulatory factor 1 to induce IL-27 production by macrophages. Furthermore, IL-27 plays a major regulatory role in vivo, because Ebi3 ؊/؊ mice can efficiently control parasite replication despite reduced levels of IFN-␥ compared to wild-type mice. On the other hand, the absence of Ebi3 leads to exacerbated IL-17A production in the infected organs as well as in a coculture system, suggesting a direct regulatory action of IL-27 during L. infantum infection. As a consequence of exacerbated IL-17A in Ebi3 ؊/؊ mice, a greater neutrophil influx was observed in the target organs, playing a role in parasite control. Thus, this work unveiled the molecular steps of IL-27 production after L. infantum infection and demonstrated its regulatory role in the IL-17A-neutrophil axis. Visceral leishmaniasis (VL), or kala-azar, is a systemic chronic disease with high mortality rates if not treated. It is caused by the parasites Leishmania infantum and L. donovani, and it is estimated that 300,000 new cases and 20,000 deaths occur annually (http://www.who.int/mediacentre/factsheets/fs375/en/). After dermal inoculation by the sandfly vector, the parasite disseminates to the liver, spleen, bone marrow, and lymph nodes of susceptible hosts, causing symptoms such as hepatosplenomegaly, lymphadenopathy, anemia, constant fever, and immunosuppression (1). Even though it is considered one of the six most important parasitic diseases affecting humans, the immunobiology of VL is not completely understood and novel therapeutic approaches are desired.The immune response against Leishmania spp. is critically mediated by gamma interferon (IFN-␥)-producing Th1 cells, which activate macrophages to produce leishmanicidal compounds, such as nitric oxide (NO) (2). Together with IFN-␥, the inflammatory cytokine interleukin-17A (IL-17A) also mediates protection against L. infantum (3, 4). On the other hand, Th2 cytokines are involved in susceptibility to leishmaniasis (2, 5). Moreover, the regulatory cytokines IL-10, IL-21, and IL-27 are produced in the bone marrow of VL patients, suggesting their association with the disease (6).The cytokine IL-27 is a dimer composed of p28...

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“…Thus, pellets from the antibiotic-treated mice enhance the activation of T cells that are cocultured with CD11b + CD11c + cells and teplizumab. IL-27 has been shown to play an important role in IL-10 expression and development of Tregs that specialize to control Th1 cell-mediated immunity (25,26). Several factors, including IL-10, TGF-β, and vitamin D have been shown to modulate DCs and induce tolerogenic DCs, which produce IL-27 (27).…”

Section: Resultsmentioning

confidence: 99%

Microbiota control immune regulation in humanized mice

Gülden¹,

Vudattu²,

Deng³

et al. 2017

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An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction

Cited by 172 publications

References 45 publications

Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation

Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation

Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17–Neutrophil Response

Microbiota control immune regulation in humanized mice

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