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TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions.

ABSTRACT: MAIT cells are an unconventional T cell population that can be activated through both TCR-dependent and TCR-independent mechanisms. Here, we examined the impact of combinations of TCR-dependent and TCR-independent signals in human CD8⁺ MAIT cells. TCR-independent activation of these MAIT cells from blood and gut was maximized by extending the panel of cytokines to include TNF-superfamily member TL1A. RNA-seq experiments revealed that TCR-dependent and TCR-independent signals drive MAIT cells to exert overlapping and specific effector functions, affecting both host defense and tissue homeostasis. Although TCR triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells showed specific enrichment of tissue-repair functions at the gene and protein levels and in in vitro assays. Altogether, these data indicate the blend of TCR-dependent and TCR-independent signaling to CD8⁺ MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair.

SUBMITTER: Leng T

PROVIDER: S-EPMC6899450 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions

Project description:We sought to describe in detail human MAIT cell activation using a transcriptomic approach to define the basic transcriptome of MAIT cells in humans and to determine how this is modulated by activation. Fresh human peripheral blood cells were obtained from three donors, and were magnetically enriched on CD8+ cells, and flow-sorted for live CD161++TCR Va7.2+ MAIT cells. These were cultured in media for 20 hours (“unstimulated”) or in the presence of anti-CD3/CD28 TCR beads (T), cytokines (IL-12, 2ng/ml, IL-18, 50ng/ml, IL-15, 25ng/ml, and TL1A, 100ng/ml), or TCR beads and cytokines combined (TC).

2019-04-17 | GSE129906 | GEO

TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions

Project description:TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions

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Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals.

Project description:Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.

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Biased MAIT TCR Usage Poised for Limited Antigen Diversity?

Project description:Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells that recognize the evolutionarily conserved major histocompatibility complex (MHC) class I-like antigen-presenting molecule known as MHC class I related protein 1 (MR1). Since their rise from obscurity in the early 1990s, the study of MAIT cells has grown substantially, accelerating our fundamental understanding of these cells and their possible roles in immunity. In the context of recent advances, we review here the relationship between MR1, antigen, and TCR usage among MAIT and other MR1-reactive T cells and provide a speculative discussion.

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MAIT Cell Activation and Functions.

Project description:Mucosal associated invariant T (MAIT) cells are striking in their abundance and their strict conservation across 150 million years of mammalian evolution, implying they must fulfill critical immunological function(s). MAIT cells are defined by their expression of a semi-invariant ?? TCR which recognizes biosynthetic derivatives of riboflavin synthesis presented on MR1. Initial studies focused on their role in detecting predominantly intracellular bacterial and mycobacterial infections. However, it is now recognized that there are several modes of MAIT cell activation and these are related to activation of distinct transcriptional programmes, each associated with distinct functional roles. In this minireview, we summarize current knowledge from human and animal studies of MAIT cell activation induced (1) in an MR1-TCR dependent manner in the context of inflammatory danger signals and associated with antibacterial host defense; (2) in an MR1-TCR independent manner by the cytokines interleukin(IL)-12/-15/-18 and type I interferon, which is associated with antiviral responses; and (3) a recently-described TCR-dependent "tissue repair" programme which is associated with accelerated wound healing in the context of commensal microbiota. Because of this capability for diverse functional responses in diverse immunological contexts, these intriguing cells now appear to be multifunctional effectors central to the interface of innate and adaptive immunity.

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MAIT cells are imprinted by the microbiota in early life and promote tissue repair.

Project description:How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T (MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury.

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Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions.

Project description:To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mitochondria. However, the signaling events that initiate aerobic glycolysis in T cells remain unclear. We show T cell activation rapidly induces glycolysis independent of transcription, translation, CD28, and Akt and not involving increased glucose uptake or activity of glycolytic enzymes. Rather, TCR signaling promotes activation of pyruvate dehydrogenase kinase 1 (PDHK1), inhibiting mitochondrial import of pyruvate and facilitating breakdown into lactate. Inhibition of PDHK1 reveals this switch is required acutely for cytokine synthesis but dispensable for cytotoxicity. Functionally, cytokine synthesis is modulated via lactate dehydrogenase, which represses cytokine mRNA translation when aerobic glycolysis is disengaged. Our data provide mechanistic insight to metabolic contribution to effector T cell function and suggest that T cell function may be finely tuned through modulation of glycolytic activity.

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Inflammatory and anti-inflammatory states of adipose tissue in transgenic mice bearing a single TCR.

Project description:Obesity is accompanied by chronic, low-grade inflammation in adipose tissue, which is associated with insulin resistance and consequent multiple metabolic diseases. In addition to M1 macrophage infiltration, multiple involvements of adipose tissue T lymphocytes in the progression of inflammation have been highlighted recently. Here, we isolated a specific V?5/V?8.2 TCR-bearing T cell that accumulated in obese adipose tissue of mice, and generated transgenic mice expressing this TCR. Under lean conditions with a normal chow diet, CD4+FoxP3+ Treg cells and M2 macrophages increased in adipose tissue with ageing in wild-type mice, but not in transgenic mice. However, both mice exhibited no obvious adipose tissue inflammation such as the formation of crown-like structures (CLSs) of infiltrating macrophages. When fed a high-fat diet, the proportion of adipose tissue Treg cells was markedly small at a similar level in transgenic and wild-type mice. Both types of mice exhibited comparable inflammatory states in adipose tissue, including vast formation of macrophage CLSs, accompanied by insulin resistance. Together, our findings suggest that the absence of an increase in Treg cells and M2 macrophages is not sufficient to initiate inflammatory macrophage infiltration in lean adipose tissue and also provide a new view about the involvement of T cells in promoting obesity-associated inflammation.

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Divergent TCR-Initiated Calcium Signals Govern Recruitment versus Activation of Human Alloreactive Effector Memory T Cells by Endothelial Cells.

Project description:Early human allograft rejection can be initiated when circulating human host versus graft Ag-specific CD8 and CD4 effector memory T cells directly recognize MHC class I and II, respectively, expressed on the luminal surface by endothelium lining graft blood vessels. TCR engagement triggers both graft entry (TCR-driven transendothelial migration or TEM) and production of proinflammatory cytokines. Both TCR-driven TEM and cytokine expression are known to depend on T cell enzymes, myosin L chain kinase, and calcineurin, respectively, that are activated by cytoplasmic calcium and calmodulin, but whether the sources of calcium that control these enzymes are the same or different is unknown. Using superantigen or anti-CD3 Ab presented by cultured human dermal microvascular cells to freshly isolated peripheral blood human effector memory T cells under conditions of flow (models of alloantigen recognition in a vascularized graft), we tested the effects of pharmacological inhibitors of TCR-activated calcium signaling pathways on TCR-driven TEM and cytokine expression. We report that extracellular calcium entry via CRAC channels is the dominant contributor to cytokine expression, but paradoxically these same inhibitors potentiate TEM. Instead, calcium entry via TRPV1, L-Type Cav, and pannexin-1/P2X receptors appear to control TCR-driven TEM. These data reveal new therapeutic targets for immunosuppression.

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Activation and In Vivo Evolution of the MAIT Cell Transcriptome in Mice and Humans Reveals Tissue Repair Functionality.

Project description:Mucosal-associated invariant T (MAIT) cells are MR1-restricted innate-like T cells conserved across mammalian species, including mice and humans. By sequencing RNA from sorted MR1-5-OP-RU tetramer+ cells derived from either human blood or murine lungs, we define the basic transcriptome of an activated MAIT cell in both species and demonstrate how this profile changes during the resolution of infection and during reinfection. We observe strong similarities between MAIT cells in humans and mice. In both species, activation leads to strong expression of pro-inflammatory cytokines and chemokines as well as a strong tissue repair signature, recently described in murine commensal-specific H2-M3-restricted T cells. Transcriptomes of MAIT cells and H2-M3-specific CD8+ T cells displayed the most similarities to invariant natural killer T (iNKT) cells when activated, but to γδ T cells after the resolution of infection. These data define the requirements for and consequences of MAIT cell activation, revealing a tissue repair phenotype expressed upon MAIT cell activation in both species.

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