Kinase-independent function of RIP1, critical for mature T-cell survival and proliferation.
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.
Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233S., 10th Street, Philadelphia, PA 19107, USA.
John P
JP
Dowling
Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233S., 10th Street, Philadelphia, PA 19107, USA.
Yubo
Y
Cai
Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
John
J
Bertin
Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
Peter J
PJ
Gough
Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233S., 10th Street, Philadelphia, PA 19107, USA.
Jianke
J
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D017353:Gene Deletion; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D013950:Thymus Gland / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D053218:Receptors, Death Domain; D014409:Tumor Necrosis Factor-alpha
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