Cutting Edge: The Ontogeny and Function of Va14Ja18 Natural T Lymphocytes Require Signal Processing by Protein Kinase Cθ and NF-κB

Abstract 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-κB signaling. However, the precise role of NF-κB in iNKT cell function and the identity of upstream signals that activate NF-κB in this T cell subset remain unknown. Using mice in which iNKT cell ontogeny has been rescued despite inhibition of NF-κB signaling, we demonstrate that iNKT cell function requires NF-κB in a lymphocyte-intrinsic manner. Furthermore, the ontogeny of functional iNKT cells requires signaling through protein kinase Cθ, which is dispensable for conventional T lymphocyte development. The unique requirement of protein kinase Cθ implies that signals emanating from the TCR activate NF-κB during iNKT cell development and function. Thus, we conclude that NF-κB signaling plays a crucial role at distinct levels of iNKT cell biology.