The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage

Abstract

Activated CD8⁺ T cells differentiate into cytotoxic effector (T_EFF) cells that eliminate target cells. How T_EFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in T_EFF cells. Runx3-deficient CD8⁺ T_EFF cells aberrantly upregulated genes characteristic of follicular helper T (T_FH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFβ transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the T_FH program. Ablating Tcf7 in Runx3-deficient CD8⁺ T_EFF cells prevented the upregulation of T_FH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing T_FH-lineage deviation.