Signal (re)processing: How disease states shape signal transduction in CD8+ T cells

Persistent antigen signaling is known to drive CD8+ T cell exhaustion (TEX) in cancer and chronic infection, but which downstream kinase cascades control this process are unknown. We found that activation of protein kinase C (PKC) triggers degradation of PKC theta while sparing PKC eta, leading to terminal TEX cells. In chronic infection, PKC theta supports progenitor exhausted (TEX-PROG) cells and maintains the antigen-specific T cell response, whereas PKC eta drives terminal exhaustion (TEX-TERM) both in vitro and in vivo. These kinases activate distinct phospho-cascades: PKC theta promotes MAPK and CDK pathways, whereas targets downstream of PKC eta include casein kinase I G2 (CK1G2). An engineered PKC theta variant resistant to degradation, or deletion of CK1G2, enhances CD8+ T cell function and tumor control. These findings reveal that TCR signaling engages distinct phospho-proteomes to regulate effector or exhausted states, opening new therapeutic avenues for T cell engineering and immunotherapy.

Speaker: Thomas Mann, Salk Institute