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A divergent transcriptional landscape underpins the development and functional branching of MAIT cells

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Science Immunology  22 Nov 2019:
Vol. 4, Issue 41, eaay6039
DOI: 10.1126/sciimmunol.aay6039

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Charting MAIT cell development

Mucosal-associated invariant T (MAIT) cells are a distinct subset of T cells that recognize vitamin B metabolites presented by MHC class I–related protein (MR1). Here, using bulk and single-cell RNA- seq and flow cytometric analysis, Koay et al. have characterized the development of murine and human MAIT cells. In addition to providing us a clearer picture of MAIT cell development in the thymus, their studies have uncovered several molecules that play key roles in regulating this process. Using knockout mouse strains, they have confirmed the functions some of these molecules, including SAP (SLAM adaptor protein), SATB1, CXCR6, and CCR7 in regulating MAIT cell development.

Abstract

MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing–based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 “mature” MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ–producing MAIT1 cells and interleukin-17–producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)–deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.

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