{"doi":"10.1073/pnas.1102779108","title":"Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity","abstract":"<jats:p>\n                    Caspase-8 (casp8) is required for extrinsic apoptosis, and mice deficient in casp8 fail to develop and die in utero while ultimately failing to maintain the proliferation of T cells, B cells, and a host of other cell types. Paradoxically, these failures are not caused by a defect in apoptosis, but by a presumed proliferative function of this protease. Indeed, following mitogenic stimulation, T cells lacking casp8 or its adaptor protein FADD (Fas-associated death domain protein) develop a hyperautophagic morphology, and die a programmed necrosis-like death process termed necroptosis. Recent studies have demonstrated that receptor-interacting protein kinases (RIPKs) RIPK1 and RIPK3 together facilitate TNF-induced necroptosis, but the precise role of RIPKs in the demise of T cells lacking FADD or casp8 activity is unknown. Here we demonstrate that RIPK3 and FADD have opposing and complementary roles in promoting T-cell clonal expansion and homeostasis. We show that the defective proliferation of T cells bearing an interfering form of FADD (FADDdd) is rescued by crossing with RIPK3\n                    <jats:sup>−/−</jats:sup>\n                    mice, although such rescue ultimately leads to lymphadenopathy. Enhanced recovery of these double-mutant T cells following stimulation demonstrates that FADD, casp8, and RIPK3 are all essential for clonal expansion, contraction, and antiviral responses. Finally, we demonstrate that caspase-mediated cleavage of RIPK1-containing necrosis inducing complexes (necrosomes) is sufficient to prevent necroptosis in the face of death receptor signaling. These studies highlight the “two-faced” nature of casp8 activity, promoting clonal expansion in some situations and apoptotic demise in others.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2011,"id":680346,"datarank":0.7254422860427218,"base_score":4.836281906951478,"endowment":4.836281906951478,"self_citation_contribution":0.7254422860427218,"citation_network_contribution":0.0,"self_endowment_contribution":0.7254422860427218,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":125,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":373174,"name":"Brian M. Weist","orcid":null,"position":1,"is_corresponding":false},{"id":1777575,"name":"Bram J. van Raam","orcid":null,"position":2,"is_corresponding":false},{"id":1777576,"name":"Brett S. Marro","orcid":null,"position":3,"is_corresponding":false},{"id":1777577,"name":"Long V. Nguyen","orcid":null,"position":4,"is_corresponding":false},{"id":1555906,"name":"Prathna Srinivas","orcid":null,"position":5,"is_corresponding":false},{"id":1777578,"name":"Bryan D. Bell","orcid":null,"position":6,"is_corresponding":false},{"id":1483491,"name":"Keith A. Luhrs","orcid":null,"position":7,"is_corresponding":false},{"id":304483,"name":"Thomas E. Lane","orcid":"0000-0003-0392-0825","position":8,"is_corresponding":false},{"id":90292,"name":"Guy S. Salvesen","orcid":"0000-0002-7933-6732","position":9,"is_corresponding":false},{"id":1089823,"name":"Craig M. Walsh","orcid":"0000-0001-7808-2817","position":10,"is_corresponding":false},{"id":1777574,"name":"Jennifer V. Lu","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity","abstract":"<jats:p>\n                    Caspase-8 (casp8) is required for extrinsic apoptosis, and mice deficient in casp8 fail to develop and die in utero while ultimately failing to maintain the proliferation of T cells, B cells, and a host of other cell types. Paradoxically, these failures are not caused by a defect in apoptosis, but by a presumed proliferative function of this protease. Indeed, following mitogenic stimulation, T cells lacking casp8 or its adaptor protein FADD (Fas-associated death domain protein) develop a hyperautophagic morphology, and die a programmed necrosis-like death process termed necroptosis. Recent studies have demonstrated that receptor-interacting protein kinases (RIPKs) RIPK1 and RIPK3 together facilitate TNF-induced necroptosis, but the precise role of RIPKs in the demise of T cells lacking FADD or casp8 activity is unknown. Here we demonstrate that RIPK3 and FADD have opposing and complementary roles in promoting T-cell clonal expansion and homeostasis. We show that the defective proliferation of T cells bearing an interfering form of FADD (FADDdd) is rescued by crossing with RIPK3\n                    <jats:sup>−/−</jats:sup>\n                    mice, although such rescue ultimately leads to lymphadenopathy. Enhanced recovery of these double-mutant T cells following stimulation demonstrates that FADD, casp8, and RIPK3 are all essential for clonal expansion, contraction, and antiviral responses. Finally, we demonstrate that caspase-mediated cleavage of RIPK1-containing necrosis inducing complexes (necrosomes) is sufficient to prevent necroptosis in the face of death receptor signaling. These studies highlight the “two-faced” nature of casp8 activity, promoting clonal expansion in some situations and apoptotic demise in others.\n                  </jats:p>","is_dataset_classified":null,"base_score":4.836281906951478,"endowment":4.836281906951478,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21876153","pmcid":"PMC3174674","openalex_id":"https://openalex.org/W2089868528","authors":[],"funders":[{"funder_name":"NINDS NIH HHS","grant_id":"NS41249","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"AI63419","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI050506","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI063419","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"AI50506","title":null},{"funder_name":"NCI NIH HHS","grant_id":"CA69381","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P01 CA069381","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA062203","title":null},{"funder_name":"NCI NIH HHS","grant_id":"T32 CA009054","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS041249","title":null}],"total_grants":10,"fwci":4.6228,"citation_percentile":0.95989837,"influential_citations":0,"citation_trend":[{"year":2012,"count":10},{"year":2013,"count":10},{"year":2014,"count":14},{"year":2015,"count":17},{"year":2016,"count":13},{"year":2017,"count":5},{"year":2018,"count":6},{"year":2019,"count":10},{"year":2020,"count":11},{"year":2021,"count":3},{"year":2022,"count":4},{"year":2023,"count":5},{"year":2024,"count":9},{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3174674","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3174674","host_type":"repository"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.1102779108","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.1102779108","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/21876153","host_type":"repository"}],"fields_of_study":["Cell death mechanisms and regulation","Phagocytosis and Immune Regulation","interferon and immune responses","Animals","CD8-Positive T-Lymphocytes","Cell Proliferation","Cell Survival","Crosses, Genetic","Fas-Associated Death Domain Protein","Female","Hepatitis, Viral, Animal","Homeostasis","Immunity","Male","Mice","Murine hepatitis virus","Receptor-Interacting Protein Serine-Threonine Kinases"],"mesh_terms":["Animals","Cell Survival","Crosses, Genetic","Female","Murine hepatitis virus","Hepatitis, Viral, Animal","Homeostasis","Immunity","Male","CD8-Positive T-Lymphocytes","Cell Proliferation","Mice","Fas-Associated Death Domain Protein","Receptor-Interacting Protein Serine-Threonine Kinases"],"keywords":["FADD","RIPK1","Necroptosis","Death domain","Cell biology","Biology","Caspase 8","Programmed cell death","TRADD","Caspase","Apoptosis","Biochemistry"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T14:54:43.722845Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}