Foxp3+ T regulatory (Treg) cells regulate immune responses and maintain self-tolerance. Recent work shows that Treg cells are comprised of many subpopulations with specialized regulatory functions. ...Here we identified Foxp3+ T cells expressing the coinhibitory molecule TIGIT as a distinct Treg cell subset that specifically suppresses proinflammatory T helper 1 (Th1) and Th17 cell, but not Th2 cell responses. Transcriptional profiling characterized TIGIT+ Treg cells as an activated Treg cell subset with high expression of Treg signature genes. Ligation of TIGIT on Treg cells induced expression of the effector molecule fibrinogen-like protein 2 (Fgl2), which promoted Treg-cell-mediated suppression of T effector cell proliferation. In addition, Fgl2 was necessary to prevent suppression of Th2 cytokine production in a model of allergic airway inflammation. TIGIT expression therefore identifies a Treg cell subset that demonstrates selectivity for suppression of Th1 and Th17 cell but not Th2 cell responses.
•TIGIT defines a distinct Foxp3+ Treg cell subset•TIGIT induces transcription and secretion of the effector molecule Fgl2 in Treg cells•TIGIT+ Treg cells suppress proinflammatory Th1 and Th17 not Th2 cell responses•Selective suppression by TIGIT+ Treg cells is Fgl2 dependent
Cytokines play a critical role in controlling the differentiation of CD4 Th cells into distinct subsets, including IL-17-producing Th17 cells. Unfortunately, the incidence of a number of autoimmune ...diseases, particularly those in which the IL-23/IL-17 axis has been implicated, has risen in the last several decades, suggesting that environmental factors can promote autoimmunity. Here we review the role of cytokines in Th17 differentiation, particularly the role of IL-23 in promoting the differentiation of a pathogenic subset of Th17 cells that potently induce autoimmune tissue inflammation. Moreover, we highlight emerging data that indicate that environmental factors, including the intestinal microbiota and changes in diet, can alter normal cytokine regulation with potent effects on Th17 differentiation and thus promote autoimmunity, which has strong implications for human disease.
Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we ...show that ILC2s expressed both the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production as well as exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.
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•ILC2s express the neuropeptide CGRP and its receptor•CGRP inhibits type 2 cytokine production and proliferation of activated ILC2s•Treatment with CGRP negatively regulates IL-33-induced airway inflammation•CGRP receptor-deficient mice show increased ILC2 responses to alarmins
Cross-talk between neurons and ILC2s regulates tissue inflammation. Here, Wallrapp et al. show that the neuropeptide CGRP negatively regulates ILC2 responses to alarmins and inhibits airway inflammation in vivo. Mice lacking the CGRP receptor have exacerbated responses to alarmins, indicating this is an important pathway that controls type 2 inflammation.
Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation, we stimulated lung nociceptors with capsaicin and observed ...increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8+ sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large-pore ion channels to specifically block nociceptors, substantially reduced ovalbumin- or house-dust-mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce the release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4+ and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma.
•Nociceptor sensory neuron ablation reduces allergic airway inflammation•QX-314 enters through large-pore ion channels to silence airway sensory neurons•IL-5 triggers sensory neuron release of peptides that drive immune cell responses•Silencing nociceptors is a new strategy to treat type 2 inflammation and allergies
Talbot et al. provide mechanistic insights into how neuro-immune interplay amplifies type 2 allergic airway inflammation. Based on this, they propose a new treatment strategy for asthma, using charged sodium channel blockers to selectively silence sensory neurons in the lung.
The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4
T ...cells promotes autoimmunity, whereas sustained overexpression on CD8
T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer
. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4
and CD8
T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.
IL-17 Blockade in Psoriasis Burkett, Patrick R.; Kuchroo, Vijay K.
Cell,
12/2016, Letnik:
167, Številka:
7
Journal Article
Recenzirano
Odprti dostop
IL-17A both directly induces and synergizes with other cytokines to promote autoimmune tissue inflammation. Secukinumab and ixekizumab are monoclonal antibodies (mAb) that inhibit interleukin-17A. ...These two agents were recently approved for treatment of psoriasis, and secukinumab is also approved for treatment of two spondyloarthropathies, psoriatic arthritis and ankylosing spondylitis.
IL-17A both directly induces and synergizes with other cytokines to promote autoimmune tissue inflammation. Secukinumab and ixekizumab are monoclonal antibodies (mAb) that inhibit interleukin-17A. These two agents were recently approved for treatment of psoriasis, and secukinumab is also approved for treatment of two spondyloarthropathies, psoriatic arthritis and ankylosing spondylitis.
Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis ...versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.
Summary
Type 2 immunity against pathogens is tightly regulated to ensure appropriate inflammatory responses that clear infection and prevent excessive tissue damage. Recent research has shown that ...type 2 innate lymphoid cells (ILC2s) contribute to steady‐state tissue integrity and exert tissue‐specific functions. However, upon exposure to inflammatory stimuli, they also initiate and amplify type 2 inflammation by inducing mucus production, eosinophilia, and Th2 differentiation. In this review, we discuss the regulation of ILC2 activation by transcription factors and metabolic pathways, as well as by extrinsic signals such as cytokines, lipid mediators, hormones, and neuropeptides. We also review recent discoveries about ILC2 plasticity and heterogeneity in different tissues, as revealed partly through single‐cell RNA sequencing of transcriptional responses to various stimuli. Understanding the tissue‐specific pathways that regulate ILC2 diversity and function is a critical step in the development of potential therapies for allergic diseases.
Signaling abnormalities in immune responses in the small intestine can trigger chronic type 2 inflammation involving interaction of multiple immune cell types. To systematically characterize this ...response, we analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA sequencing (scRNA-seq) at steady state and after induction of a type 2 inflammatory reaction to ovalbumin (OVA). Computational analysis revealed broad shifts in both cell-type composition and cell programs in response to the inflammation, especially in group 2 innate lymphoid cells (ILC2s). Inflammation induced the expression of exon 5 of Calca, which encodes the alpha-calcitonin gene-related peptide (α-CGRP), in intestinal KLRG1+ ILC2s. α-CGRP antagonized KLRG1+ ILC2s proliferation but promoted IL-5 expression. Genetic perturbation of α-CGRP increased the proportion of intestinal KLRG1+ ILC2s. Our work highlights a model where α-CGRP-mediated neuronal signaling is critical for suppressing ILC2 expansion and maintaining homeostasis of the type 2 immune machinery.
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•scRNA-seq reveals intestinal immune cell programs in allergic inflammation•Intestinal KLRG1+ ILC2s express α-CGRP and its receptors•α-CGRP regulates type 2 cytokine production of KLRG1+ ILC2s•α-CGRP maintains KLRG1+ ILC2 homeostasis and the type 2 immune machinery
Allergic inflammation involves the interaction of multiple immune cell types, as well as their crosstalk with other physiological systems, such as neurons. By establishing intestinal immune cell atlas at different states, Xu et al. identify that neuropeptide α-CGRP modulates group 2 innate lymphoid cell responses and the allergic reaction.
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