TCR- or Cytokine-Activated CD8+ Mucosal-Associated Invariant T Cells Are Rapid Polyfunctional Effectors That Can Coordinate Immune Responses

Abstract

Graphical AbstractHighlights d RNA sequencing of MAIT cells following stimulation via T cell receptor or cytokines d TCR and cytokines induce distinct transcriptome with different modes of activation d TCR stimuli result in a rapid, polyfunctional, proinflammatory response d Cytokine stimulation results in a slower, more restricted response SUMMARY Mucosal-associated invariant T (MAIT) cells can be activated via either their T cell receptor (TCR), which recognizes MR1-bound pyrimidines derived from microbial riboflavin biosynthesis, or via cytokines. These two modes of activation may act in concert or independently, depending upon the stimulus. It is unknown, however, how MAIT cell responses differ with the mode of activation. Here, we define transcriptional and effector responses of human CD8 + MAIT cells to TCR and cytokine stimulation. We report that MAIT cells rapidly respond to TCR stimulation, producing multiple cytokines and chemokines, altering their cytotoxic granule content and transcription factor expression, and upregulating co-stimulatory proteins. In contrast, cytokine-mediated activation is slower and results in a more limited response. Therefore, we propose that, in infections by riboflavin-synthesizing bacteria, MAIT cells play a key early role in effecting and coordinating immune responses, while in the absence of TCR stimulation, their role is likely to differ.

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

“…First, in all 3 cases, a GSEA analysis using TCR-triggered MAIT cells revealed a statistically robust congruence with the tissue-repair signature. In both studies in which this was addressed, this was not seen with cytokine stimulation alone (IL-12/IL-18 in the parallel study) (Lamichhane et al, 2019). Looking more broadly at transcriptional regulation of MAIT cells in mouse and man, the data fusion analyses also showed a strong link between the activation of human MAIT cells shown here (and in parallel studies) and the Tc17 tissue-repair subset of Linehan et al (2018).…”

“…A similar set of RNA-seq data, functional data, and conclusions has been obtained using parallel experiments in human MAIT cells ex vivo with a 5-OP-RU and bacterial trigger and most importantly in an in vivo challenge incorporating a TCR trigger with and without cytokines (Hinks et al, 2019;Lamichhane et al, 2019). Several observations can be made from a comparison of the transcriptional data.…”

“…Taking together the data here and those of Hinks et al (2019) and Lamichhane et al (2019), we propose a model whereby in the human gut and potentially in the liver, MAIT cells are continuously exposed to MR1-bound ligand derived from the commensal bacteria present in the microbiome. In the absence of inflammatory signals, this only drives the circumscribed transcriptional signature associated with local homeostatic function.…”

“…Finally, we performed, using an extension of this bioinformatic approach, alignment among all 3 generated datasets on human and mouse MAIT cell activation to assess their comparability. All 3 have shown that under conditions in which the TCR is stimulated, there is a tissue-repair signature, but when tested in both our dataset and that of Lamichhane et al (2019), the statistical association in gene set enrichment analysis (GSEA) studies was lost under conditions of cytokine stimulation alone. In Figure S6, all unstimulated human MAIT cells clustered (indicating both good data fusion and consistency between studies), with (E) Visualization of the CD8 + MAIT cell transcripts elicited by differential stimulations in the subspace of the first principle components (PCs).…”

“…CD161-expressing human TCR lymphocytes possess shared transcriptional and functional phenotypes, and their enhanced innate ability to respond to inflammatory cues has been investigated with transcriptomic approaches (Fergusson et al, 2014). MAIT cells comprise a large proportion of these CD161-expressing T cells and have previously been described as showing limited responses to conventional TCR signals, although combinatorial signaling can markedly augment this in vitro and in vivo (Slichter et al, 2016;Turtle et al, 2011) (see also accompanying papers by Hinks et al, 2019, andLamichhane et al, 2019). However, MAIT cells can respond in a fully TCR-independent manner, via cytokine signaling, and such behavior can trigger protection in vivo (Wilgenburg et al, 2018).…”