The transcription factor IRF8 promotes the survival of differentiated effector CD8 T cells 2254435
Abstract
CD8+ T cells depend on IL-2 signals to drive effector differentiation and sustain clonal expansion, yet how IL-2—responsive transcription factors coordinate these outcomes remains incompletely defined. The transcription factor IRF8, previously known for roles in myeloid and B-cell lineage reinforcement, is highly sensitive to IL-2 signals in CD8+ T cells. We hypothesized that IRF8 integrates IL-2—dependent transcriptional programs to support effector differentiation in CD8+ T cells. Equal numbers of congenically marked WT and IRF8-deficient cells (generated by conditional deletion or CRISPR/Cas9 editing) were co-transferred into recipients that were either given acute (Listeria-OVA) or chronic (B16-OVA, MC38-OVA bearing hosts) antigen challenges. Effector differentiation, persistence, and function were evaluated by flow cytometry While IRF8 expression is minimal at the peak of the acute response, CTLs generated during Listeria-OVA infection induce IRF8 when cultured in the presence of IL-2 in a dose-dependent manner. IRF8-deficient cells form fewer SLECs at day 7 p.i., and exhibit a stark defect in persistence during the contraction phase. In chronic antigen models, significantly fewer IRF8-deficient cells are recoverable from the tumor, tumor-draining lymph node, and spleens of B16-OVA and MC38-OVA bearing mice compared to WT. This finding is supported by higher levels of the pro-apoptotic protein Bim in these cells. Conversely, forced overexpression of IRF8 in adoptively transferred cells in this model provides a competitive survival advantage indicated by greater numbers and lower expression of Bim over WT. These findings position IRF8 as a cytokine-sensitive transcription factor that orchestrates the transcriptional control of apoptotic restraint, promoting sustained fitness and survival in effector CD8 T cells. Our work highlights the potential for overexpression of IRF8 during adoptive cell therapy regimens as a strategy for enhancing their long-term persistence. CU School of Medicine Startup Award NIH R01A01043957 Lymphocyte Differentiation and Peripheral Maintenance (LYM)