BATF regulates progenitor to cytolytic effector CD8⁺ T cell transition during chronic viral infection

During chronic viral infection, CD8⁺ T cells develop into three major phenotypically and functionally distinct subsets: Ly108⁺TCF-1⁺ progenitors, Ly108^-CX₃CR1^- terminally exhausted cells and the recently identified CX₃CR1⁺ cytotoxic effector cells. Nevertheless, how CX₃CR1⁺ effector cell differentiation is transcriptionally and epigenetically regulated remains elusive. Here, we identify distinct gene regulatory networks and epigenetic landscapes underpinning the formation of these subsets. Notably, our data demonstrate that CX₃CR1⁺ effector cells bear a striking similarity to short-lived effector cells during acute infection. Genetic deletion of Tbx21 significantly diminished formation of the CX₃CR1⁺ subset. Importantly, we further identify a previously unappreciated role for the transcription factor BATF in maintaining a permissive chromatin structure that allows the transition from TCF-1⁺ progenitors to CX₃CR1⁺ effector cells. BATF directly bound to regulatory regions near Tbx21 and Klf2, modulating their enhancer accessibility to facilitate the transition. These mechanistic insights can potentially be harnessed to overcome T cell exhaustion during chronic infection and cancer.