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The death domain kinase RIP protects thymocytes from tumor necrosis factor receptor type 2-induced cell death.

Cusson N, Oikemus S, Kilpatrick ED, Cunningham L, Kelliher M - J. Exp. Med. (2002)

Bottom Line: We observed a decrease in rip-/- thymocytes and T cells in both wild-type C57BL/6 and recombination activating gene 1-/- irradiated hosts.However, rip-deficient mice contain few viable CD4+ and CD8+ thymocytes, and rip-/- thymocytes are sensitive to TNF-induced cell death.Taken together, this study implicates RIP and TNFR2 in thymocyte survival.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

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DP thymocyte survival in the absence of rip and tnfr2. To determine the contribution of TNFR2 to rip−/− thymocyte apoptosis, thymus was harvested at day 2 from rip−/−/tnfr2−/− mice and control littermates. Thymocytes were stained with PE–anti-CD4 and FITC–anti-CD8. Viable cells expressing CD4 and CD8 are shown. Six rip−/−/tnfr2−/− and 36 control littermates were analyzed. Two representative plots are shown for rip−/−/tnfr2−/− mice.
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fig7: DP thymocyte survival in the absence of rip and tnfr2. To determine the contribution of TNFR2 to rip−/− thymocyte apoptosis, thymus was harvested at day 2 from rip−/−/tnfr2−/− mice and control littermates. Thymocytes were stained with PE–anti-CD4 and FITC–anti-CD8. Viable cells expressing CD4 and CD8 are shown. Six rip−/−/tnfr2−/− and 36 control littermates were analyzed. Two representative plots are shown for rip−/−/tnfr2−/− mice.

Mentions: In the absence of TNFR1, rip−/− DP thymocytes undergo apoptosis and fail to survive, which suggests that rip−/− and rip−/−/tnfr1−/− thymocytes may undergo TNFR2-induced cell death. The TNFR2 (p75) has also been implicated in immune homeostasis (for review see reference 8). To test whether the thymocyte apoptosis observed in the rip−/−/tnfr1−/− mice is TNFR2-mediated, we examined the neonatal rip+/−/tnfr2−/− and rip−/−/tnfr2−/− thymus. In contrast to the decreased cellularity observed in the rip−/− and rip−/−/tnfr1−/− thymus, the neonatal rip−/−/tnfr2−/− thymus contained similar numbers of total thymocytes as control littermates (Fig. 7 A). Surprisingly, in the absence of rip and TNFR2, no decreases in the relative percentage of DP thymocytes were observed (Fig. 7 B). Similar numbers of DP thymocytes were detected in rip−/−/tnfr2−/− mice (72, 84, 82, 95, and 92%) as seen in littermate controls (86, 83, 85, 93, 92, and 90%). Consistent with these studies, no significant increase in the percent of apoptotic cells was observed (unpublished data). These studies implicate TNFR2 in DP thymocyte survival and suggest that rip participates in TNFR2 signaling.


The death domain kinase RIP protects thymocytes from tumor necrosis factor receptor type 2-induced cell death.

Cusson N, Oikemus S, Kilpatrick ED, Cunningham L, Kelliher M - J. Exp. Med. (2002)

DP thymocyte survival in the absence of rip and tnfr2. To determine the contribution of TNFR2 to rip−/− thymocyte apoptosis, thymus was harvested at day 2 from rip−/−/tnfr2−/− mice and control littermates. Thymocytes were stained with PE–anti-CD4 and FITC–anti-CD8. Viable cells expressing CD4 and CD8 are shown. Six rip−/−/tnfr2−/− and 36 control littermates were analyzed. Two representative plots are shown for rip−/−/tnfr2−/− mice.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2194008&req=5

fig7: DP thymocyte survival in the absence of rip and tnfr2. To determine the contribution of TNFR2 to rip−/− thymocyte apoptosis, thymus was harvested at day 2 from rip−/−/tnfr2−/− mice and control littermates. Thymocytes were stained with PE–anti-CD4 and FITC–anti-CD8. Viable cells expressing CD4 and CD8 are shown. Six rip−/−/tnfr2−/− and 36 control littermates were analyzed. Two representative plots are shown for rip−/−/tnfr2−/− mice.
Mentions: In the absence of TNFR1, rip−/− DP thymocytes undergo apoptosis and fail to survive, which suggests that rip−/− and rip−/−/tnfr1−/− thymocytes may undergo TNFR2-induced cell death. The TNFR2 (p75) has also been implicated in immune homeostasis (for review see reference 8). To test whether the thymocyte apoptosis observed in the rip−/−/tnfr1−/− mice is TNFR2-mediated, we examined the neonatal rip+/−/tnfr2−/− and rip−/−/tnfr2−/− thymus. In contrast to the decreased cellularity observed in the rip−/− and rip−/−/tnfr1−/− thymus, the neonatal rip−/−/tnfr2−/− thymus contained similar numbers of total thymocytes as control littermates (Fig. 7 A). Surprisingly, in the absence of rip and TNFR2, no decreases in the relative percentage of DP thymocytes were observed (Fig. 7 B). Similar numbers of DP thymocytes were detected in rip−/−/tnfr2−/− mice (72, 84, 82, 95, and 92%) as seen in littermate controls (86, 83, 85, 93, 92, and 90%). Consistent with these studies, no significant increase in the percent of apoptotic cells was observed (unpublished data). These studies implicate TNFR2 in DP thymocyte survival and suggest that rip participates in TNFR2 signaling.

Bottom Line: We observed a decrease in rip-/- thymocytes and T cells in both wild-type C57BL/6 and recombination activating gene 1-/- irradiated hosts.However, rip-deficient mice contain few viable CD4+ and CD8+ thymocytes, and rip-/- thymocytes are sensitive to TNF-induced cell death.Taken together, this study implicates RIP and TNFR2 in thymocyte survival.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

Show MeSH
Related in: MedlinePlus