Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation

Invariant NKT (iNKT) cells are an innate type of T cells, which respond rapidly on activation. iNKT cells acquire these innate-like abilities during development; however, the signals driving development and functional maturation remain only partially understood. Because interleukin-15 (IL-15) is crucial for iNKT development and is delivered by transpresentation, we set out to identify the cell types providing IL-15 to developing iNKT cells and determine their role at the various states of development and maturation. We report here that transpresentation of IL-15 by parenchymal cells was crucial for generating normal number of iNKTs in the thymus, whereas both hematopoietic and parenchymal cells regulated iNKT cell numbers in the periphery, particularly in the liver. Specifically, dendritic cells contributed to peripheral iNKT cell numbers by up-regulating Bcl-2 expression and promoting extrathymic iNKT cell expansion and their homeostatic proliferation. Whether IL-15 affects functional ;maturation of iNKT cells was also examined. In IL-15R(alpha)(-/-) mice, CD44(High)NK1.1(+) iNKT cells displayed decreased T-bet expression and in response to alpha-galactosylceramide, had deficient interferon-gamma expression. Such defects could be reversed by exogenous IL-15 signals. Overall, these studies identify stage-specific functions of IL-15, which are determined by the tissue microenvironment and elucidate the importance of IL-15 in functional maturation. (Blood. 2010;116(14):2494-2503)