Propagation of TCR signals through distinct PKC pathways determines T cell effector and exhaustion states 3137

The Journal of Immunology 2025

Thomas H. Mann; Hannah M. Knox; Shixin Ma; Jesse Furgiuele; Anna-Maria Globig; Michael LaPorte; H. Kay Chung; Bryan McDonald; Majid Ghassemian; Steven Zhao; Hubert Tseng; Yagmur Farsakoglu; Victoria Tripple; Johnny Koo; Alexandra C. Newton; Susan M. Kaech

Abstract

Abstract Description Persistent antigen signaling is known to drive CD8+ T cell exhaustion (TEX) in cancer and chronic infection, but the role of downstream kinase cascades remains unclear. 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. Funding Sources Supported by NIH/NCI T32CA009370; NIH/NIAID 5R01AI066232; NIH/NCI 5R01CA216101; Cancer Research Institute CRI4859; Damon Runyon Cancer Research Foundation DRG2358-19; Salary support via sponsored research with Arvinas. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

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