Cutting edge:: The ontogeny and function of Va14Ja18 natural T lymphocytes require signal processing by protein kinase Cθ and NF-κB

The rapid and robust immunoregulatory cytokine response of Va14Ja18 natural T (iNKT) cells to glycolipid Ags determines their diverse functions. Unlike conventional T cells, iNKT lymphocyte ontogeny absolutely requires NF-kappaB signaling. However, the precise role of NF-kappaB in iNKT cell function and the identity of upstream signals that activate NF-kappaB in this T cell subset remain unknown. Using mice in which iNKT cell ontogeny has been rescued despite inhibition of NF-kappaB signaling, we demonstrate that iNKT cell function requires NF-kappaB in a lymphocyte-intrinsic manner. Furthermore, the ontogeny of functional iNKT cells requires signaling through protein kinase Ctheta, which is dispensable for conventional T lymphocyte development. The unique requirement of protein kinase Ctheta implies that signals emanating from the TCR activate NF-kappaB during iNKT cell development and function. Thus, we conclude that NF-kappaB signaling plays a crucial role at distinct levels of iNKT cell biology.