Survival of mature T cells depends on signaling through HOIP.

Abstract

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[Δlinear] 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[Δlinear] CD4[+] T cells failed to phosphorylate IκBα and JNK through T cell receptor-mediated stimulation. Mature CD4[+] and CD8[+] T cells in T-HOIP[Δlinear] mice underwent apoptosis more rapidly than control T cells, and it was accompanied by lower CD127 expression on CD4[+]CD24[low] and CD8[+]CD24[low] T cells in the thymus. The enforced expression of CD127 in T-HOIP[Δlinear] 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.