Different signaling interpretations by PKC eta and theta control T cell function and exhaustion
Year: 2024
Type: preprint
Abstract: SUMMARY Chronic antigen signaling drives CD8 + T cell exhaustion (T EX ) 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 T EX cells. During chronic infection, PKC theta is necessary to maintain the progenitor exhausted (T EX-PROG ) cells, and thus the antigen-specific T cell response, while agonism of PKC eta promotes terminal exhaustion (T EX-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 T EX differentiation and its clinical potential in cancer immunotherapy. Highlights PKC theta sustains T cell function while PKC eta promotes terminal exhaustion PKC theta and eta drive distinct phospho-cascades to oppose each other’s differentiation instructions An engineered, degradation-resistant PKC theta improves T cell responses in chronic infection and cancer Ablation of kinase CK1G2 downstream of PKC eta improves anti-tumor T cell responses
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4402906995