Evidence for a RIPK1-independent survival mechanism for CASPASE-8 in αβ T cells

Abstract

CASPASE8 promotes both cell death and survival by acting as a trigger of apoptosis but also a repressor of necroptosis. In T cells, CASPASE8 is required for FAS induced apoptosis, but protects activated T cells from necroptosis. The broader role and mechanisms of CASPASE8 in the wider T cell compartment is less certain. Here, we analysed mice in which Casp8 was conditionally deleted in the lymphoid compartment by huCD2iCre. In the thymus, we found evidence of a modest impairment of early thymic progenitors and a striking absence of NKT cell development. Amongst mature peripheral T cells, there was a substantial and specific reduction in the CD8 T cell compartment, that included naive, central memory and virtual memory subsets. While life spans and turnover of CD8 T cells appeared largely normal, we did identify an acute requirement for continued CASPASE8 expression for survival of a fraction of CD8 T cells, since induced Casp8 deletion by tamoxifen induced CD8CreERT resulted in an acute loss of CD8 T cells. CASPASE8 deficient T cells were resistant to FAS or TNF induced cell death in vitro. Generating Casp8 deficient mice that express a kinase dead RIPK1 confirmed that necroptosis contributed to death of thymic progenitors and some peripheral CD8 T cell subsets in the absence of CASPASE8. However, kinase dead RIPK1 failed to restore NKT cell development and only partially rescued CD8 VM T cells, while analysing mixed bone marrow chimeras suggested that CASPASE8 deficient CD4 and CD8 T cells were less competitively fit than WT T cells, even in the absence of RIPK1 kinase activity. These latter observations suggest the existence of a novel mechanism by which CASPASE8 promotes T cell survival that is independent of its established role in repressing necroptosis.