{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["31(6)"],"submitter":["Huysentruyt J"],"pubmed_abstract":["The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we demonstrate that conditional ablation of Ripk1 in conventional T cells (Ripk1<sup>ΔCD4</sup>) causes peripheral T cell lymphopenia, as witnessed by a profound loss of naive CD4<sup>+</sup>, naive CD8<sup>+</sup>, and FoxP3<sup>+</sup> regulatory T cells. Interestingly, peripheral naive CD8<sup>+</sup> T cells in Ripk1<sup>ΔCD4</sup> mice appear to undergo a selective pressure to retain RIPK1 expression following activation. Mixed bone marrow chimeras revealed a competitive survival disadvantage for naive, effector, and memory T cells lacking RIPK1. Additionally, tamoxifen-induced deletion of RIPK1 in CD4-expressing cells in adult life confirmed the importance of RIPK1 in post-thymic survival of CD4<sup>+</sup> T cells. Ripk1<sup>K45A</sup> mice showed no change in peripheral T cell subsets, demonstrating that the T cell lymphopenia was due to the scaffold function of RIPK1 rather than to its kinase activity. Enhanced numbers of Ripk1<sup>ΔCD4</sup> naive T cells expressed the proliferation marker Ki-67<sup>+</sup> despite the peripheral lymphopenia and single-cell RNA sequencing revealed T cell-specific transcriptomic alterations that were reverted by additional caspase-8 deficiency. Furthermore, Ripk1<sup>ΔCD4</sup>Casp8 <sup>ΔCD4</sup> and Ripk1<sup>ΔCD4</sup>Tnfr1<sup>-/-</sup> double-knockout mice rescued the peripheral T cell lymphopenia, revealing that RIPK1-deficient naive CD4<sup>+</sup> and CD8<sup>+</sup> cells and FoxP3<sup>+</sup> regulatory T cells specifically die from TNF- and caspase-8-mediated apoptosis in vivo. Altogether, our findings emphasize the essential role of RIPK1 as a scaffold in maintaining the peripheral T cell compartment and preventing TNFR1-induced apoptosis."],"journal":["Cell death and differentiation"],"pagination":["820-832"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11164875"],"repository":["biostudies-literature"],"pubmed_title":["RIPK1 protects naive and regulatory T cells from TNFR1-induced apoptosis."],"pmcid":["PMC11164875"],"pubmed_authors":["Ruiz Perez M","Huysentruyt J","Flies K","Lambrecht BN","Verstraeten B","Tougaard P","Steels W","Vanden Berghe T","Divert T","Vandenabeele P","Takahashi N","Maelfait J","Declercq W","Vadi M"],"additional_accession":[]},"is_claimable":false,"name":"RIPK1 protects naive and regulatory T cells from TNFR1-induced apoptosis.","description":"The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we demonstrate that conditional ablation of Ripk1 in conventional T cells (Ripk1<sup>ΔCD4</sup>) causes peripheral T cell lymphopenia, as witnessed by a profound loss of naive CD4<sup>+</sup>, naive CD8<sup>+</sup>, and FoxP3<sup>+</sup> regulatory T cells. Interestingly, peripheral naive CD8<sup>+</sup> T cells in Ripk1<sup>ΔCD4</sup> mice appear to undergo a selective pressure to retain RIPK1 expression following activation. Mixed bone marrow chimeras revealed a competitive survival disadvantage for naive, effector, and memory T cells lacking RIPK1. Additionally, tamoxifen-induced deletion of RIPK1 in CD4-expressing cells in adult life confirmed the importance of RIPK1 in post-thymic survival of CD4<sup>+</sup> T cells. Ripk1<sup>K45A</sup> mice showed no change in peripheral T cell subsets, demonstrating that the T cell lymphopenia was due to the scaffold function of RIPK1 rather than to its kinase activity. Enhanced numbers of Ripk1<sup>ΔCD4</sup> naive T cells expressed the proliferation marker Ki-67<sup>+</sup> despite the peripheral lymphopenia and single-cell RNA sequencing revealed T cell-specific transcriptomic alterations that were reverted by additional caspase-8 deficiency. Furthermore, Ripk1<sup>ΔCD4</sup>Casp8 <sup>ΔCD4</sup> and Ripk1<sup>ΔCD4</sup>Tnfr1<sup>-/-</sup> double-knockout mice rescued the peripheral T cell lymphopenia, revealing that RIPK1-deficient naive CD4<sup>+</sup> and CD8<sup>+</sup> cells and FoxP3<sup>+</sup> regulatory T cells specifically die from TNF- and caspase-8-mediated apoptosis in vivo. Altogether, our findings emphasize the essential role of RIPK1 as a scaffold in maintaining the peripheral T cell compartment and preventing TNFR1-induced apoptosis.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jun","modification":"2025-04-04T12:47:52.538Z","creation":"2025-04-04T12:47:52.538Z"},"accession":"S-EPMC11164875","cross_references":{"pubmed":["38734851"],"doi":["10.1038/s41418-024-01301-w"]}}