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RIPK1 blocks T cell senescence mediated by RIPK3 and caspase-8.


ABSTRACT: Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation. Here, we show that T cell-specific RIPK1 deficiency in mice leads to the premature senescence of T cells and induces various age-related diseases, resulting in premature death. RIPK1 deficiency causes higher basal activation of mTORC1 (mechanistic target of rapamycin complex 1) that drives enhanced cytokine production, induction of senescence-related genes, and increased activation of caspase-3/7, which are restored by inhibition of mTORC1. Critically, normal aged T cells exhibit similar phenotypes and responses. Mechanistically, a combined deficiency of RIPK3 and caspase-8 inhibition restores the impaired proliferative responses; the elevated activation of Akt, mTORC1, extracellular signal-regulated kinase, and caspase-3/7; and the increased expression of senescence-related genes in RIPK1-deficient CD4 T cells. Last, we revealed that the senescent phenotype of RIPK1-deficient and aged CD4 T cells is restored in the normal tissue environment. Thus, we have clarified the function of RIPK3 and caspase-8 in inducing CD4 T cell senescence, which is modulated by environmental signals.

SUBMITTER: Imanishi T 

PROVIDER: S-EPMC9876550 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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RIPK1 blocks T cell senescence mediated by RIPK3 and caspase-8.

Imanishi Takayuki T   Unno Midori M   Yoneda Natsumi N   Motomura Yasutaka Y   Mochizuki Miho M   Sasaki Takaharu T   Pasparakis Manolis M   Saito Takashi T  

Science advances 20230125 4


Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation. Here, we show that T cell-specific RIPK1 deficiency in mice leads to the premature senescence of T cells and induces various age-related diseases, resulting in premature death. RIPK1 deficiency causes higher basal activation of mTORC1 (mechanistic target of rapamycin complex 1) that drives enhanced cytokine production, induction of senescence-related genes, and increased activation of caspase-3/7, which are rest  ...[more]

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