Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers

Abstract

Exhausted CD8+ T (TEX) cells undergo extensive genome reorganization during differentiation, yet the drivers of this process remain elusive. Here we show that CTCF programmed CD8+ TEX cell fates through two distinct modes of action. CTCF acquired de novo binding sites and concordantly induced open chromatin in early CD8+ TEX cells responding to chronic viral infection. The dynamic CTCF binding activated enhancers and promoted chromatin looping. Consequently, genetic ablation of CTCF diminished chromatin accessibility and interaction strength, impairing CD8+ TEX cell proliferation, effector function and bioenergetic mobilization. Conversely, invariant CTCF binding acted as essential chromatin barriers, and loss of CTCF disrupted insulation and caused aberrant chromatin self-association and undue RNA polymerase II pausing, leading to excessive activation of exhaustion- and stemness-linked genes. Thus, CTCF balanced CD8+ TEX cell differentiation by gaining dynamic binding to induce cytotoxicity and sustain metabolic fitness, while its invariant binding compartmentalized exhaustion and stemness program genes to prevent their overexuberant activation. Xue and colleagues show that the chromatin regulator CTCF balances stemness preservation and effector differentiation to specify CD8+ TPEX versus CD8+ TEX_EFF cell fate decisions.