Kinase-independent function of RIP1, critical for mature T-cell survival and proliferation

John P Dowling,Jianke Zhang,Peter J Gough,John Bertin,Yubo Cai

doi:10.1038/cddis.2016.307

Abstract

The death receptor, Fas, triggers apoptotic death and is essential for maintaining homeostasis in the peripheral lymphoid organs. RIP1 was originally cloned when searching for Fas-binding proteins and was later shown to associate also with the signaling complex of TNFR1. Although Fas exclusively induces apoptosis, TNFR1 primarily activates the pro-survival/pro-inflammatory NF-κB pathway. Mutations in Fas lead to lymphoproliferative (lpr) diseases, and deletion of TNFR1 results in defective innate immune responses. However, the function of RIP1 in the adult lymphoid system has not been well understood, primarily owing to perinatal lethality in mice lacking the entire RIP1 protein in germ cells. This current study investigated the requirement for RIP1 in the T lineage using viable RIP1 mutant mice containing a conditional and kinase-dead RIP1 allele. Disabling the kinase activity of RIP1 had no obvious impact on the T-cell compartment. However, T-cell-specific deletion of RIP1 led to a severe T-lymphopenic condition, owing to a dramatically reduced mature T-cell pool in the periphery. Interestingly, the immature T-cell compartment in the thymus appeared intact. Further analysis showed that mature RIP1−/− T cells were severely defective in antigen receptor-induced proliferative responses. Moreover, the RIP1−/− T cells displayed greatly increased death and contained elevated caspase activities, an indication of apoptosis. In total, these results revealed a novel, kinase-independent function of RIP1, which is essential for not only promoting TCR-induced proliferative responses but also in blocking apoptosis in mature T cells.

Highlights

T lymphopoiesis as well as maintenance of the mature population.[1,2] Apoptosis is a major programmed cell death pathway, which can be induced through either intrinsic or extrinsic signals.[3]
RIP1 associates with the signaling complex of tumor necrosis factor receptor 1 (TNFR1) or Fas, neither of the two death receptors was essential during mouse development or lymphocyte development
Prior studies have indicated that RIP1 may be essential for T-cell development, because RIP1− / − fetal liver cells failed to reconstitute the T-cell compartment of immune-deficient recipient mice,[15,26] and mice lacking RIP1 in hematopoietic stem cells and progenitors (HSCs/Ps) contain few T cells.[27]

Summary

Introduction

T lymphopoiesis as well as maintenance of the mature population.[1,2] Apoptosis is a major programmed cell death pathway, which can be induced through either intrinsic or extrinsic signals.[3]. RIP1− / − FADD− / − double knockout (DKO) mice display perinatal lethality,[15] similar to the phenotype of RIP1− / − single knockout mice.[10] In contrast, deletion of a RIP1-related protein kinase, RIP3, fully restores normal embryonic as well as postnatal development in FADD− / − mice.[21] Recent studies demonstrated that RIP1− / − mice can only reach adulthood when both FADD and RIP3 are absent, indicating that RIP1 protects neonatal cells from FADD-mediated apoptosis and RIP3-dependent necroptosis.[22,23,24,25] Importantly, FADD− / − RIP3− / − DKO mice and RIP1− / − FADD− / − RIP3− / − triple knockout mice develop age-dependent lymphadenopathy and splenomegaly, reminiscent of the lymphoproliferative (lpr) disease displayed by Fas− / − mice Both apoptosis and necroptosis are essential for homeostasis in the peripheral lymphoid organs

Methods

Results

Conclusion