Single-cell transcriptional profiling reveals signatures of helper, effector, and regulatory MAIT cells during homeostasis and activation Journal Article

Authors: Vorkas, C. K.; Krishna, C.; Li, K.; Aubé, J.; Fitzgerald, D. W.; Mazutis, L.; Leslie, C. S.; Glickman, M. S.
Article Title: Single-cell transcriptional profiling reveals signatures of helper, effector, and regulatory MAIT cells during homeostasis and activation
Abstract: Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that recognize microbial vitamin B metabolites and have emerging roles in infectious disease, autoimmunity, and cancer. Although MAIT cells are identified by a semi-invariant TCR, their phenotypic and functional heterogeneity is not well understood. Here we present an integrated single cell transcriptomic analysis of over 76,000 human MAIT cells during early and prolonged Ag-specific activation with the MR1 ligand 5-OP-RU and nonspecific TCR stimulation. We show that MAIT cells span a broad range of homeostatic, effector, helper, tissue-infiltrating, regulatory, and exhausted phenotypes, with distinct gene expression programs associated with CD4+ or CD8+ coexpression. During early activation, MAIT cells rapidly adopt a cytotoxic phenotype characterized by high expression of GZMB, IFNG and TNF In contrast, prolonged stimulation induces heterogeneous states defined by proliferation, cytotoxicity, immune modulation, and exhaustion. We further demonstrate a FOXP3 expressing MAIT cell subset that phenotypically resembles conventional regulatory T cells. Moreover, scRNAseq-defined MAIT cell subpopulations were also detected in individuals recently exposed to Mycobacterium tuberculosis, confirming their presence during human infection. To our knowledge, our study provides the first comprehensive atlas of human MAIT cells in activation conditions and defines substantial functional heterogeneity, suggesting complex roles in health and disease. Copyright © 2022 by The American Association of Immunologists, Inc.
Keywords: genetics; cd8+ t lymphocyte; cell proliferation; cd8-positive t-lymphocytes; forkhead transcription factors; cytology; metabolism; cells, cultured; gene expression profiling; immunology; lymphocyte activation; mycobacterium tuberculosis; tumor necrosis factor-alpha; gamma interferon; cell culture; receptors, antigen, t-cell; cd4+ t lymphocyte; cd4-positive t-lymphocytes; interferon-gamma; homeostasis; forkhead transcription factor; transcriptome; lymphocyte antigen receptor; foxp3 protein, mouse; tumor necrosis factor; granzymes; single cell analysis; single-cell analysis; uracil; granzyme; humans; human; gzmb protein, mouse; ifng protein, mouse; mucosal-associated invariant t cell; 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil; ribitol; tnf protein, mouse; mucosal-associated invariant t cells
Journal Title: Journal of Immunology
Volume: 208
Issue: 5
ISSN: 0022-1767
Publisher: The American Association of Immunologists, Inc  
Date Published: 2022-03-01
Start Page: 1042
End Page: 1056
Language: English
DOI: 10.4049/jimmunol.2100522
PUBMED: 35149530
PROVIDER: scopus
PMCID: PMC9012082
Notes: Article -- Export Date: 1 April 2022 -- Source: Scopus
Citation Impact
MSK Authors
  1. Michael Glickman
    104 Glickman
  2. Christina Leslie
    165 Leslie
  3. Chirag Krishna
    20 Krishna
  4. Charles Vorkas
    8 Vorkas
  5. Linas Mazutis
    28 Mazutis