Human MAITregs possess diverse TCR repertoires and are functionally supported by glycolysis.

Mucosal-associated invariant T (MAIT) regulatory cells (MAITregs) represent a specialized subset with immunosuppressive functions, yet their properties and molecular basis are largely unknown. We demonstrate that MAITregs, while sharing T cell receptor (TCR) repertoires with conventional MAIT cells, undergo selective clonal expansion during in vitro generation, leading to biased V(D)J profiles and restricted CDR3 diversity. Moreover, integrated transcriptomics revealed that MAITregs preferred glycolysis, which was supported by chromatin remodeling at glycolytic gene loci. Functionally, glycolysis in MAITregs favored their IL-10 production but inhibited Th1 cytokines, whereas oxidative phosphorylation (OXPHOS) promoted their Th1/Th17 cytokines. Our study defines MAITregs as a clonally expanded population whose regulatory potency is strictly governed by cellular metabolism.