Human MAIT cells undergo clonal selection and expansion during thymic maturation and aging

Area of Science:

• Immunology
• T cell biology
• Human thymic development

Background:

• Mucosal-associated invariant T (MAIT) cells possess conserved T cell receptors (TCRs) that recognize riboflavin metabolites.
• Despite conserved TCRs, MAIT cells display significant diversity akin to conventional memory T cells.
• The developmental mechanisms shaping MAIT cell diversity within the thymus are not well understood.

Purpose of the Study:

• To investigate the thymic ontogeny and diversity-shaping mechanisms of human MAIT cells.
• To compare MAIT cell maturation with other unconventional T cell populations.

Main Methods:

• Analysis of 37 human thymic MAIT cell samples across different ages.
• Comparative analysis with invariant natural killer T (iNKT) and gamma delta (γδ) T cells.
• Assessment of cell surface markers (CD27, CD161) and gene expression related to tissue residency.

Main Results:

• CD27 and CD161 identify maturation stages in MAIT, iNKT, and Vγ9+Vδ2+ γδ T cells.
• Mature CD161+ MAIT cells exhibit clonal expansion with aging and increased tissue residency gene expression.
• MAIT cell diversity is established by diverse CDR3β sequences, which decrease during maturation.
• A subset of MAIT cells (25%) express dual TCRα transcripts, indicating origin from double-positive thymocytes.

Conclusions:

• Thymic MAIT cell development involves dynamic repertoire selection processes.
• MAIT cell maturation mirrors aspects of conventional T cell development, including diversity regulation.
• These findings elucidate key mechanisms governing MAIT cell repertoire formation in the human thymus.