A conserved transcriptional program for MAIT cells across mammalian evolution.

Area of Science:

• Immunology
• Evolutionary Biology
• Cellular Biology

Background:

• Mucosal-associated invariant T (MAIT) cells possess conserved T cell receptors (TCRs), implying critical roles.
• Discrepancies in human and mouse MAIT cell functions obscure their conserved evolutionary features.

Purpose of the Study:

• To investigate the evolutionary conserved functional characteristics of MAIT cells.
• To identify conserved transcriptional events during MAIT cell maturation across diverse species.

Main Methods:

• Employed species-specific tetramers combined with single-cell RNA sequencing.
• Analyzed MAIT cell development across six species, covering 110 million years of evolutionary history.

Main Results:

• Identified conserved ZBTB16 induction as a key marker of MAIT cell maturation across all studied species.
• Observed a shared type-1/17 transcriptional program in MAIT cells from humans, sheep, cattle, and opossums, suggesting ancestral characteristics.
• Noted that human invariant natural killer T (iNKT) cells also acquired this type-1/17 program, indicating common differentiation pathways for innate-like T cells.
• Documented the development of distinct type-1 and type-17 MAIT cell subsets in rodents.
• Revealed that mouse intestinal MAIT cells acquire a highly conserved program involving type-1, type-17, cytotoxicity, and tissue-repair genes.

Conclusions:

• MAIT cell maturation involves conserved transcriptional events, including ZBTB16 induction, across a wide evolutionary range.
• Innate-like T cells, including MAIT and iNKT cells, share common differentiation pathways.
• Rodent MAIT cells exhibit specialized subsets, with intestinal MAIT cells in mice displaying a unique, conserved program for cytotoxicity and tissue repair.