Ontogeny of human mucosal-associated invariant T cells and related T cell subsets

Mucosal-associated invariant T (MAIT) cells are semi-invariant V alpha 7.2(+) CD161(high)CD4(-)T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied V alpha 7.2(+) CD161(high) T cell and related subset levels in infancy and after cord blood transplantation. We show that V alpha 7.2(+) and V alpha 7.2(-) CD161(high) T cells are generated early during gestation and likely share a common prenatal developmental program. Among cord blood V alpha 7.2(+) CD161(high) T cells, the minority recognizing MR1 : 5-OP-RU display a TRAV/TRBV repertoire very similar to adult MAIT cells. Within a few weeks of life, only the MR1 : 5-OP-RU reactive V alpha 7.2(+) CD161(high) T cells acquire a memory phenotype. Only these cells expand to form the adult MAIT pool, diluting out other V alpha 7.2(+) CD161(high) and V alpha 7.2(-) CD161(high) populations, in a process requiring at least 6 years to reach adult levels. Thus, the high clonal size of adult MAIT cells is antigen-driven and likely due to the fine specificity of the TCR alpha beta chains recognizing MR1-restricted microbial antigens.