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.

在慢性病毒感染期间，CD8 ⁺ T 细胞发育成三个主要的表型和功能不同的亚群：Ly108 ⁺ TCF-1 ⁺祖细胞、Ly108 ^- CX ₃ CR1 ^-终末衰竭细胞和最近发现的 CX ₃ CR1 ⁺细胞毒性效应细胞。然而，CX ₃ CR1 ⁺效应细胞分化如何在转录和表观遗传学上受到调控仍然是个谜。在这里，我们确定了支持这些子集形成的不同基因调控网络和表观遗传景观。值得注意的是，我们的数据表明 CX ₃ CR1 ⁺效应细胞与急性感染期间的短寿命效应细胞具有惊人的相似性。Tbx21的遗传缺失显着减少了 CX ₃ CR1 ⁺子集的形成。重要的是，我们进一步确定了转录因子 BATF 在维持允许从 TCF-1 ⁺祖细胞过渡到 CX ₃ CR1 ⁺效应细胞的染色质结构中的先前未被重视的作用。BATF 直接绑定到Tbx21和Klf2附近的监管区域, 调节它们的增强器可访问性以促进过渡。这些机制的见解有可能被用来克服慢性感染和癌症期间的 T 细胞耗竭。