2025/01/01 by Farjana Islam, Scott Layzell, Inês Boal‐Carvalho +1 · 1 voice
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · #Cell death mechanisms and regulation #Phagocytosis and Immune Regulation #Ubiquitin and proteasome pathways
paper · pdf · doi:10.1093/discim/kyaf016
openalex publication_date 2025/01/01 · openalex created_date 2025/11/29 · openalex updated_date 2026/07/29
Abstract Introduction CASPASE8 promotes both cell death and survival by acting as a trigger of apoptosis and a repressor of necroptosis. In T cells, the function and mechanisms of CASPASE8 are incompletely understood. Methods Here, we analysed mice in which Casp8 was conditionally deleted in T cells at different stages of development. Results In mice with deletion early in T cell development, we observed a modest reduction in early thymic progenitors and a striking absence of NKT cells in the thymus. Amongst mature peripheral T cells, there was a substantial and specific reduction in the CD8 T cell compartment, which included naive, central memory and virtual memory subsets. Using a tamoxifen-inducible CD8CreERT to delete Casp8 revealed an acute requirement for continued CASPASE8 expression for survival of a fraction of mature CD8 T cells. Analysing Casp8-deficient mice that express a kinase dead RIPK1 suggested that in vivo, necroptosis contributed to death of thymic progenitors and CD8EM and CD8CM subsets. However, kinase dead RIPK1 failed to restore NKT cell development or rescue the loss of CD4EM and CD4CM in mixed bone marrow chimeras, and only partially rescued CD8 VM T cell. Conclusions Together, these observations suggest that CASPASE8 promotes T cell survival independent of its established role in repressing RIPK1-dependent necroptosis.