Different signaling interpretations by PKC eta and theta control T cell function and exhaustion

Abstract

Chronic antigen signaling drives CD8+ T cell exhaustion (TEX) in cancer and chronic infection. However, how the kinase cascades downstream of the T cell receptor drive exhaustion is not understood. We found that continuous agonism of protein kinase C (PKC) causes degradation of PKC theta, but not PKC eta, and induces terminal TEX cells. During chronic infection, PKC theta is necessary to maintain the progenitor exhausted (TEX-PROG) cells, and thus the antigen-specific T cell response, while agonism of PKC eta promotes terminal exhaustion (TEX-TERM) in vitro and in vivo. The cascades downstream of these kinases are distinct, with PKC theta promoting activity of canonical PKC targets in the MAPK and CDK families, while eta promotes activity of other targets, including casein kinase I G2 (CK1G2). Expression of an engineered, degradation-resistant PKC theta, or deletion of the gene encoding CK1G2, improves T cell function and tumor control. Our illustration of multiple therapeutic avenues arising from targeting PKC highlights its centrality in TEX differentiation and its clinical potential in cancer immunotherapy. HighlightsO_LIPKC theta sustains T cell function while PKC eta promotes terminal exhaustion C_LIO_LIPKC theta and eta drive distinct phospho-cascades to oppose each others differentiation instructions C_LIO_LIAn engineered, degradation-resistant PKC theta improves T cell responses in chronic infection and cancer C_LIO_LIAblation of kinase CK1G2 downstream of PKC eta improves anti-tumor T cell responses C_LI