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

Tianqi Leng,Joachim Hagel,Hossain Delowar Akther,Mastura Neyazi,Carl-Philipp Hackstein,Emanuele Marchi,Matthias Friedrich,Raphael Sanches Peres,Sarah Mccuaig,Val Millar,Kate Powell,Paul Klenerman,Daniel Ebner,Rajesh Lamichhane,Fiona Powrie,Carolina V Arancibia‐Cárcamo ,C Willberg ,Tsc Hinks ,T P King ,James E Ussher ,Z Christoforidou

doi:10.1016/j.celrep.2019.08.050

Abstract

SummaryMAIT 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.

Highlights

Human innate and adaptive immune systems form a critical partnership in immune defense against microorganisms
It has been shown to increase production of IFN-g and Tumor necrosis factor (TNF)-a by CD161+CD4+ T cells in the presence of anti-CD3 or IL12+IL-18 (Jin et al, 2013). This may be relevant to mucosal-associated invariant T (MAIT) cell functions, because we have previously identified a phenotypic, functional, and transcriptional program shared by CD161-expressing cells (Fergusson et al, 2014)
We find that IL-12 and IL-18, in synergy with T cell receptor (TCR) triggering, promote the activation of MAIT cells and that additional TL1A signaling can optimize this response in a dose-dependent manner

Summary

Introduction

Human innate and adaptive immune systems form a critical partnership in immune defense against microorganisms. MAIT cells are abundant in human blood and enriched most substantially in the liver (Dusseaux et al, 2011). They are marked by high surface expression of the C-type lectin molecule CD161, and they bear the semi-invariant T cell receptor (TCR) Va7.2-Ja33/12/20, which restricts them to the evolutionary conserved, non-polymorphic major histocompatibility complex (MHC) class I-related protein 1 (MR1) (Kjer-Nielsen et al, 2012; Reantragoon et al, 2013). MR1 tetramers loaded with riboflavin and folate intermediates have been developed, enabling the specific detection and characterization of human and mouse MAIT cells (LopezSagaseta et al, 2013; Rahimpour et al, 2015; Reantragoon et al, 2013)

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Discussion

Conclusion