A novel double edged sword in T cell development and function: Receptor-Interacting Protein Kinase 1 (RIPK1)

Abstract Ripk1 is a key regulator of survival and death. This dual function is controlled by post-translational modifications: ubiquitination of RIPK1 leads to activation and survival whereas its deubiquitination or phosphorylation triggers death. In addition to its involvement in downstream signaling by many death receptors RIPK1 also functions in TCR-induced signaling cascades that either lead to activation-induced death or survival and NFkb activation. The role of Ripk1 in T cells development and functions are still poorly understood mainly because of the perinatal lethality of Ripk1 genomic deletion. To circumvent this problem, we generated T cell specific conditional KO mice by crossed Ripk1fl/fl mice with CD4-Cre. This deletion during development greatly affected the generation of TCRab thymocytes and in particular the agonist selected T cell subsets, including the NKT cells and the TCRab DN T cells. Similarly, TCRab T cells in the periphery were greatly reduced, in particular the NK T cell and DN subsets, whereas as expected TCRgd T cells were not affected. Most remaining TCRab T cells displayed a CD44+ activated phenotype and differentiation to cytotoxic cells, including the CD4 T cells. A similar effect was seen among the mucosal T cells in the gut, where few DN T cells were present and most of the intraepithelial TCRab T cells were cytotoxic CD8 T cells with high levels of Granzyme expression. All CD4 IETs were negative for ThPOK and expressed granzyme similar to their CD8 counterparts. These observations highlight an important role for RIPK1 in thymic development of agonist selected T cells as well as conventional CD4 and CD8 thymocytes and in the periphery for the functional maturation and survival of lymphoid and tissue resident T cell subsets