CTCF is necessary for CD8+ effector T cell differentiation

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Abstract Naive T cell differentiation into effector and memory subsets in response to infection requires the coordination of numerous factors that regulate changes in gene expression to support proliferation and cell function. Chromatin accessibility and DNA looping influence transcription factor binding, facilitate enhancer-promoter interactions, and insulate genes. CCCTC-Binding Factor (CTCF) is a highly conserved protein important for organizing the genome and partnering with transcription factors, but its role in CD8+ T cell differentiation has yet to be determined. We show that loss of CTCF in CD8+ T cells alters the expression of genes important for subset differentiation and these changes are reflected during Listeria infection where the formation of memory-precursor cells is favored while the formation of terminal effector cells is impaired. At a memory timepoint, CTCF knockdown enhances intestinal Trm accumulation despite impairing circulating memory maintenance. ChIP-Seq and HiC reveals that terminal effector cells gain CTCF binding within topologically associated domains, often overlapping with H3K27ac peaks which marks active enhancers and promoters. As genes near the overlap of CTCF and H3K27ac peaks have increased expression in terminal effector cells, we propose that one role of CTCF is to promote effector function by stabilizing promoter-enhancer interactions which influences the expression of fate-determining genes. Insights into the role of CTCF in CD8+ T cell differentiation during infection will yield valuable insight into dynamic chromatin changes regulating T cell differentiation and inform the development of therapies which better utilize the T cell response.