Swarbrick, GM; Gela, A; Cansler, ME; Null, MD; Duncan, RB; Nemes, E; Shey, M; ... Lewinsohn, DA; + view all Swarbrick, GM; Gela, A; Cansler, ME; Null, MD; Duncan, RB; Nemes, E; Shey, M; Nsereko, M; Mayanja-Kizza, H; Kiguli, S; Koh, J; Hanekom, WA; Hatherill, M; Lancioni, C; Lewinsohn, DM; Scriba, TJ; Lewinsohn, DA; - view fewer (2020) Postnatal Expansion, Maturation, and Functionality of MR1T Cells in Humans. Frontiers in Immunology , 11 , Article 556695. 10.3389/fimmu.2020.556695.

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Abstract

MR1-restricted T (MR1T) cells are defined by their recognition of metabolite antigens presented by the monomorphic MHC class 1-related molecule, MR1, the most highly conserved MHC class I related molecule in mammalian species. Mucosal-associated invariant T (MAIT) cells are the predominant subset of MR1T cells expressing an invariant TCR α-chain, TRAV1-2. These cells comprise a T cell subset that recognizes and mediates host immune responses to a broad array of microbial pathogens, including Mycobacterium tuberculosis. Here, we sought to characterize development of circulating human MR1T cells as defined by MR1-5-OP-RU tetramer labeling and of the TRAV1-2^{+} MAIT cells defined by expression of TRAV1-2 and high expression of CD26 and CD161 (TRAV1-2^{+}CD161^{++}CD26^{++} cells). We analyzed postnatal expansion, maturation, and functionality of peripheral blood MR1-5-OP-RU tetramer^{+} MR1T cells in cohorts from three different geographic settings with different tuberculosis (TB) vaccination practices, levels of exposure to and infection with M. tuberculosis. Early after birth, frequencies of MR1-5-OP-RU tetramer^{+} MR1T cells increased rapidly by several fold. This coincided with the transition from a predominantly CD4^{+} and TRAV1-2^{−} population in neonates, to a predominantly TRAV1-2^{+}CD161^{++}CD26^{++}CD8^{+} population. We also observed that tetramer^{+} MR1T cells that expressed TNF upon mycobacterial stimulation were very low in neonates, but increased ~10-fold in the first year of life. These functional MR1T cells in all age groups were MR1-5-OP-RU tetramer^{+}TRAV1-2^{+} and highly expressed CD161 and CD26, markers that appeared to signal phenotypic and functional maturation of this cell subset. This age-associated maturation was also marked by the loss of naïve T cell markers on tetramer^{+} TRAV1-2^{+} MR1T cells more rapidly than tetramer^{+}TRAV1-2^{−} MR1T cells and non-MR1T cells. These data suggest that neonates have infrequent populations of MR1T cells with diverse phenotypic attributes; and that exposure to the environment rapidly and preferentially expands the MR1-5-OP-RU tetramer^{+}TRAV1-2^{+} population of MR1T cells, which becomes the predominant population of functional MR1T cells early during childhood.

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