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bioRxiv · 10.1101/2019.12.20.882746

Postnatal expansion, maturation and functionality of MR1 T cells in humans

Swarbrick, G. M.·Gela, A.·Cansler, M. E.·Null, M. D.·Duncan, R. B.·Nemes, E.·Shey, M.·Nsereko, M.·Mayanja-Kizza, H.·Kiguli, S.·Koh, J.·Hanekom, W.·Hatherill, M.·Lancioni, C.·Lewinsohn, D. M.·Scriba, T.·Lewinsohn, D. A.
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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 -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 labelling 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 analysed 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 naive 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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Swarbrick, G. M., Gela, A., Cansler, M. E., Null, M. D., Duncan, R. B., Nemes, E., Shey, M., Nsereko, M., Mayanja-Kizza, H., Kiguli, S., Koh, J., Hanekom, W., Hatherill, M., Lancioni, C., Lewinsohn, D. M., Scriba, T., Lewinsohn, D. A.. 2019-12-21. Postnatal expansion, maturation and functionality of MR1 T cells in humans. https://doi.org/10.1101/2019.12.20.882746

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