TGF-β Promotes the Postselection Thymic Development and Peripheral Function of IFN-γ-Producing Invariant NKT cells

IFN-γproducing invariant NKT (iNKT)1 cells are lipid-reactive innate-like lymphocytes that are resident in the thymus and peripheral tissues where they protect against pathogenic infection. The thymic functions of iNKT1 cells are not fully elucidated, but subsets of thymic iNKT cells modulate CD8 T cell, dendritic cell, B cell, and thymic epithelial cell numbers or function. In this study, we show that a subset of murine thymic iNKT1 cells required TGF-βinduced signals for their postselection development, to maintain hallmark TGF-βinduced genes, and for expression of the adhesion receptors CD49a and CD103. However, the residency-associated receptor CD69 was not TGFβ signalinγdependent. Recently described CD244+ c2 thymic iNKT1 cells, which produce IFNγ without exogenous stimulation and have NK-like characteristics, reside in this TGF-βresponsive population. Liver and spleen iNKT1 cells do not share this TGFβ gene signature, but nonetheless TGFβ impacts liver iNKT1 cell phenotype and function. Our findings provide insight into the heterogeneity of mechanisms guiding iNKT1 cell development in different tissues and suggest a close association between a subset of iNKT1 cells and TGF-βproducing cells in the thymus that support their development. The Journal of Immunology, 2023, 211: 1376-1384.