Early-life imprinting of unconventional T cells and tissue homeostasis

Unconventional T cells—including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and defined subsets of γδ T cells—are restricted by monomorphic major histocompatibility complex class Ib (MHC-Ib) molecules and seed tissues during development. Early-life instructive signals, including those derived from the microbiota, establish homeostatic set points for unconventional T cells, a phenomenon that has lifelong consequences for the regulation of tissue immunity, inflammation, and repair. Unconventional T cells compete for niches within tissues, and recent evidence supports the idea that the fundamental role of these cells in tissue physiology may result from their action as a network with overlapping and potentially synergistic functions, rather than as individual subsets.