Innate-like activation of mucosal-associated invariant T cells in mycobacterial infection

Abstract Unlike conventional T cells, mucosal-associated invariant T (MAIT) T cells respond to microbial riboflavin precursor metabolites presented by major histocompatibility complex (MHC)-like molecule MHC-related protein 1 (MR1). Recently, a high percentage of CD8+ T cells reactive to Mycobacterium tuberculosis in humans were identified as MAIT cells instead of conventional MHC class I-restricted T cells. To understand the activation mechanism and effector functions of MAIT cells in mycobacterial infections, we used mycobacterial-incubated human dendritic cells and MR1-overexpressed cells to stimulate primary and clonal human MAIT cells. As a result, the enzyme-linked immunospot assay showed a quick activation kinetics of MAIT cells within hours of mycobacterial stimulation in an MR1-dependent manner. Flow cytometry analysis demonstrated that mycobacterial-incubated antigen presenting cells quickly stimulated primary human MAIT cells to develop a dominant CD69+CD26+phenotype. Activated MAIT cells displayed an enhanced expression of cytokines TNFa, IFNg, IL-17, and granulysin, demonstrating a potential to induce pro-inflammatory and cytolytic responses. Further transcriptomic analysis of the CD69+CD26+subset revealed an integrated activation pathway from conventional CD8+ T cells and natural killer (NK) cells. Especially, activated MAIT cells showed an enhanced gene expression of mitogen-activated protein kinase (MAPK) signaling molecules, NF-kB, T-bet, RORg, and PLZF transcription factors, and pro-inflammatory cytokines and cytolytic molecules. Taken together, our data support that MAIT cells are quickly activated through an innate-like activation mechanism to induce anti-mycobacterial responses.