Journal
FRONTIERS IN IMMUNOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.01136
Keywords
mucosal-associated invariant T (MAIT) cells; transcriptome; MHC-related protein 1 (MR1); Mycobacterium tuberculosis; innate-like activation
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Funding
- National Institute of Allergy and Infectious Diseases [AI115358]
- American Lung Association [IA-629987]
- National Institute of Environmental Health Sciences [ES006096]
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Conventional T cells exhibit a delayed response to the initial priming of peptide antigens presented by major histocompatibility complex (MHC) proteins. Unlike conventional T cells, mucosal-associated invariant T (MAIT) cells quickly respond to non-peptidic metabolite antigens presented by MHC-related protein 1 (MR1). To elucidate the MR1-dependent activation program of MAIT cells in response to mycobacterial infections, we determined the surface markers, transcriptomic profiles, and effector responses of activated human MAIT cells. Results revealed that mycobacterial-incubated antigen-presenting cells stimulated abundant human CD8(+)MAIT cells to upregulate the co-expression of CD69 and CD26, as a combinatorial activation marker. Further transcriptomic analyses demonstrated that CD69(+)CD26(++)CD8(+)MAIT cells highly expressed numerous genes for mediating anti-mycobacterial immune responses, including pro-inflammatory cytokines, cytolytic molecules, NK cell receptors, and transcription factors, in contrast to inactivated counterparts CD69(+/-)CD26(+/-)CD8(+)MAIT cells. Gene co-expression, enrichment, and pathway analyses yielded high statistical significance to strongly support that activated CD8(+)MAIT cells shared gene expression and numerous pathways with NK and CD8(+)T cells in activation, cytokine production, cytokine signaling, and effector functions. Flow cytometry detected that activated CD8(+)MAIT cells produced TNF alpha, IFN gamma, and granulysin to inhibit mycobacterial growth and fight mycobacterial infection. Together, results strongly support that the combinatorial activation marker CD69(+)CD26(++)labels the activated CD8(+)MAIT cells that develop an innate-like activation program in anti-mycobacterial immune responses. We speculate that the rapid production of anti-mycobacterial effector molecules facilitates MAIT cells to fight early mycobacterial infection in humans.
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