Capicua mediates interleukin-2 withdrawal-induced death of activated CD8+ T cells.

During the course of an immune response, antigen-reactive T cells undergo clonal expansion and are subsequently eliminated by cytokine withdrawal-induced cell death (CWID), an intrinsic apoptotic program essential for immune homeostasis. However, the mechanisms orchestrating CWID remain poorly understood. Here, we performed genome-wide CRISPR-Cas9 knockout screens in CTLL-2 cells, which identified the transcriptional repressor Capicua (CIC) as a critical mediator of CWID. CIC mediates CWID but not apoptosis induced by staurosporine or etoposide. Deficiency of CIC attenuates IL-2 withdrawal-induced death of mouse primary CD8+ but not CD4+ T cells. CIC promotes CWID via a BIM-independent pathway, and simultaneous deletion of CIC and BIM fully abrogates CWID. Although CIC is activated upon IL-2 withdrawal to repress its target genes, its role in CWID is independent of its transcriptional repression. Instead, CIC promotes CWID by facilitating Cullin-3/KEAP1-mediated BCL2 degradation and disrupting the BAX-BCL2 interaction. In a Listeria monocytogenes infection model, CIC-deficiency suppresses apoptosis of activated CD8+ T cells, resulting in their increase in the later phase of infection. Our findings suggest that CIC plays a vital role in CWID through a noncanonical mechanism, providing new insights into how the immune system limits uncontrolled inflammation and immunopathology.