Human and murine MAIT cells share many characteristics (specificity, phenotype and effector activities) with the exception that 1) murine MAIT cells already acquire a memory (CD44^hi) phenotype in the thymus and do not expand much in the periphery while human MAIT cells are naïve at birth in the cord blood before acquiring a memory phenotype and expanding to reach high clonal size in adulthood. 2) In mice, MAIT cells can be divided into two subsets expressing either T-bet or RORgt, the latter being the most abundant. In contrast, human MAIT cells simultaneously express T-bet, RORgt, EOMES and IKZF2 (Helios).

In human cord blood, Va7.2^-CD161^high T cells are more abundant than the Va7.2⁺ subset. Measurements of Va7.2⁺CD161^high and related subsets (Va7.2^-CD161^high and NKT) in infants of different gestational ages indicate that Va7.2⁺ and Va7.2^- CD161^high T cells undergo an early wave of thymic development during gestation, and likely share a common prenatal developmental program. CD161^high T cell (either Va7.2⁺ or Va7.2^-) frequencies in the cord blood are highly correlated between twins irrespective of the homo or hetero-zygotic status, indicating that prenatal environmental factors may control their development. Contrary to adult blood, in which virtually all Va7.2⁺ CD161^high T cells are labeled with MR1:5-OP-RU tet, only a small proportion of Va7.2⁺ CD161^high T cells in cord blood are stained by the tetramer. Interestingly, these cells display a TRAV and TRBV repertoire very similar to adult MAIT cells. A few days after birth, all Va7.2⁺ CD161^high T cells acquire a memory phenotype and few week later, the great majoriy is labeled with MR1:5-OP-RU tetramer. This suggests that only the MR1:5-OP-RU-reactive cells expand in the periphery, diluting out other Va7.2⁺ CD161^high and Va7.2^- CD161^high populations. Still, it takes five to six years to reach adult MAIT cells frequencies. Our data suggest that the high clonal size of adult MAITs is antigen-driven and likely due to the fine specificity of the TCR a and b chains allowing recognition of MR1-restricted microbial antigens.

Altogether, our data emphasize the importance of environmental factors in shaping MAIT cell development. Moreover, the two-step development pathway of MAIT cells occurs in the thymus in mice while the final maturation step occurs in the periphery after birth in humans.