Regulation of NF-κB-dependent T cell activation and development by MEKK3

The serine/threonine kinase MEKK3, also known as mitogen-activated protein kinase kinase kinase 3, is a critical activator of the transcription factor NF-kappa B in innate immunity. However, the physiological function of MEKK3 in adaptive immunity is unclear. Here we report that following TCR signaling, MEKK3 positively regulated the kinase, I kappa B kinase, leading to NF-kappa B activation. T cells lacking MEKK3 were defective in TCR-induced and cytokine-induced responses. Furthermore, T cell-specific deletion of MEKK3 resulted in reduced numbers of thymocytes and peripheral T cells. Thus, our results provide genetic evidence that MEKK3 plays a crucial role in adaptive immunity.