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The death domain kinase RIP protects thymocytes from tumor necrosis factor receptor type 2-induced cell death
Nicole Cusson1, Sarah Oikemus, Elizabeth D Kilpatrick
1Department of Molecular Genetics and Microbiology, Program in Immunology/Virology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Abstract:
Fas and the tumor necrosis factor receptor (TNFR)1 regulate the programmed cell death of lymphocytes. The death domain kinase, receptor interacting protein (rip), is recruited to the TNFR1 upon receptor activation. In vitro, rip-/- fibroblasts are sensitive to TNF-induced cell death due to an impaired nuclear factor kappaB response. Because rip-/- mice die at birth, we were unable to examine the effects of a targeted rip mutation on lymphocyte survival. To address the contribution of RIP to immune homeostasis, we examined lethally irradiated mice reconstituted with rip-/- hematopoietic precursors. We observed a decrease in rip-/- thymocytes and T cells in both wild-type C57BL/6 and recombination activating gene 1-/- irradiated hosts. In contrast, the B cell and myeloid lineages are unaffected by the absence of rip. Thus, the death domain kinase rip is required for T cell development. Unlike Fas-associated death domain, rip does not regulate T cell proliferation, as rip-/- T cells respond to polyclonal activators. However, rip-deficient mice contain few viable CD4+ and CD8+ thymocytes, and rip-/- thymocytes are sensitive to TNF-induced cell death. Surprisingly, the rip-associated thymocyte apoptosis was not rescued by the absence of TNFR1, but appears to be rescued by an absence of TNFR2. Taken together, this study implicates RIP and TNFR2 in thymocyte survival.
Insights
Receptor interacting protein (RIP) is crucial for T cell development and survival. RIP deficiency leads to reduced thymocytes and T cells, impacting immune homeostasis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Fas and tumor necrosis factor receptor (TNFR)1 are key regulators of programmed lymphocyte death.
- Receptor interacting protein (RIP) is a death domain kinase recruited to TNFR1 upon activation.
- RIP deficiency in fibroblasts impairs TNF-induced cell death due to reduced nuclear factor kappaB response.
Purpose of the Study:
- To investigate the role of RIP in immune homeostasis and T cell development.
- To address the effects of RIP deficiency on lymphocyte survival in vivo.
Main Methods:
- Utilized lethally irradiated mice reconstituted with RIP-deficient (rip-/-) hematopoietic precursors.
- Analyzed thymocyte and T cell populations in wild-type and recombination activating gene 1-/- hosts.
- Assessed T cell proliferation in response to polyclonal activators.
- Investigated the role of TNFR1 and TNFR2 in RIP-associated thymocyte apoptosis.
Main Results:
- RIP is essential for T cell development, as evidenced by decreased rip-/- thymocytes and T cells.
- B cell and myeloid lineages were unaffected by RIP deficiency.
- RIP-deficient thymocytes exhibited sensitivity to TNF-induced cell death.
- Thymocyte apoptosis was rescued by the absence of TNFR2, but not TNFR1.
Conclusions:
- The death domain kinase RIP is required for T cell development and thymocyte survival.
- RIP plays a critical role in immune homeostasis, specifically within the T cell lineage.
- RIP and TNFR2 are implicated in regulating thymocyte survival, highlighting a novel pathway in T cell development.