Survival of mature T cells depends on signaling through HOIP.

T cell development in the thymus is controlled by a multistep process. The NF-κB pathway regulates T cell development as well as T cell activation at multiple differentiation stages. The linear ubiquitin chain assembly complex (LUBAC) is composed of Sharpin, HOIL-1L and HOIP, and it is crucial for regulating the NF-κB and cell death pathways. However, little is known about the roles of LUBAC in T-cell development and activation. Here, we show that in T-HOIP mice lacking the ubiquitin ligase activity of LUBAC, thymic CD4 or CD8 T cell numbers were markedly reduced with severe defects in NKT cell development. HOIP CD4 T cells failed to phosphorylate IκBα and JNK through T cell receptor-mediated stimulation. Mature CD4 and CD8 T cells in T-HOIP mice underwent apoptosis more rapidly than control T cells, and it was accompanied by lower CD127 expression on CD4CD24 and CD8CD24 T cells in the thymus. The enforced expression of CD127 in T-HOIP thymocytes rescued the development of mature CD8 T cells. Collectively, our results showed that LUBAC ligase activity is key for the survival of mature T cells, and suggest multiple roles of the NF-κB and cell death pathways in activating or maintaining T cell-mediated adaptive immune responses.