Stepwise development of MAIT cells in mouse and human

Area of Science:

• Immunology
• T cell biology
• Innate immunity

Background:

• Mucosal-associated invariant T (MAIT) cells are a unique T cell population characterized by an invariant T cell receptor alpha (iTCRalpha) chain and restriction by the MHC class Ib molecule MR1.
• MAIT cell development is poorly understood, with limited data on their presence and maturation within the thymus.

Purpose of the Study:

• To elucidate the stepwise process of MAIT cell development in both human and mouse models.
• To investigate the roles of MR1, B cells, commensal flora, and specific molecular factors in MAIT cell ontogeny.

Main Methods:

• Utilized complementary human and mouse experiments, including anti-human Valpha7.2 antibody, MAIT cell-specific iTCRalpha and TCRbeta transgenic mice, and adoptive transfer of B cells.
• Analyzed MAIT cell phenotypes (naïve, memory) and transcription factor expression (ZBTB16) in thymus, cord blood, and peripheral blood.
• Investigated MR1-dependent selection in fetal thymic organ culture and RAG knockout models.

Main Results:

• MAIT cell development is a stepwise process involving intra-thymic selection and peripheral expansion.
• MR1-dependent selection occurs in the thymus, but peripheral accumulation requires MR1-expressing B cells and commensal flora.
• Human MAIT cells mature postnatally, acquiring a memory phenotype, while mouse MAIT cells initially display a naïve phenotype and lack ZBTB16 expression.

Conclusions:

• MAIT cells are selected in the thymus by MR1 on non-T, non-B hematopoietic cells.
• Peripheral expansion and memory phenotype acquisition depend on B cells and gut microbiota.
• MAIT cell development presents a unique pathway distinct from NKT and gammadelta T cells.