Postnatal expansion, maturation and functionality of MR1T cells in humans

MR1-restricted T (MR1T) cells are 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 defined by MR1-5-OP-RU tetramer labelling and expression of TRAV1-2/CD26/CD161. We analysed postnatal expansion, maturation and functionality of peripheral blood 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-defined MR1T cells increased rapidly by several fold. This coincided with marked phenotypic changes, from a predominantly CD4⁺ and TRAV1-2⁻ phenotype in neonates, to predominantly TRAV1-2⁺CD8⁺ MR1T cells that also expressed CD26 and CD161. 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⁺ cells and expressed CD26 and CD161, 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. Author Summary MR1-restricted T (MR1T) cells defend against many microbial infections that cause illness and death in young children, including Mycobacterium tuberculosis, which causes tuberculosis (TB). Here, we characterized the development of human MR1T cells from after birth to adulthood. We analysed expansion, maturation and functionality of MR1T cells in populations from three different geographic settings with different tuberculosis vaccination practices and levels of exposure to and infection with M. tuberculosis. We found that early after birth, MR1T cells were rare but then expanded rapidly coinciding with marked phenotypic changes, from heterogeneous phenotypes in neonates, to one predominant type of MR1T cells in adults. We also observed that MR1T cells that defend against mycobacteria were rare in neonates but then increased ~10-fold in the first year of life. We also observed that MR1T cells matured more rapidly than other types of T cells. Our data suggest that neonates have rare populations of MR1T cells with diverse phenotypes and that exposure to the environment rapidly and preferentially expands a dominant population of MR1T cells early during childhood. Our data improves our understanding of the human development of MR1T cells relevant to important childhood pathogens, which could aid in the improvement of infant vaccines.