Bcl11b regulates multipotency and effector programs in intestinal resident memory CD8+ T cells
Journal of Immunology(2023)
Abstract
Abstract Tissue-resident memory CD8 +T cells (Trm) reside in non-lymphoid tissues and provide potent protection from re-infection. They are multipotent and have diverse functions, including effector roles during re-infection. Using a series of RNA-seq, ATAC-seq, ChIP-seq and CUT&RUN experiments, we investigated Bcl11b-dependent molecular mechanisms governing the differentiation of small intestine Trm cells. Mice with conditionally depleted Bcl11b in activated CD8 +T cells had largely altered memory T cell populations. Particularly the Trm cells and their precursors displayed strong transcriptional deregulation. Regions with decreased ATAC-seq and/or H3K27ac signal in Bcl11b-deficient cells were enriched for DNA binding motifs associated with the multifunctional/multipotent Trm program, whereas regions with increased signal for the motifs associated with the effector program. Correspondingly, genes from the multifunctional/multipotent and effector programs had decreased and increased expression in Bcl11b-deficient cells, respectively. Most of the program genes were bound by Bcl11b and displayed related epigenetic changes in Bcl11b-deficient cells. These results were experimentally validated for Tcf1 and Ahr, which exhibited increased binding at regions with decreased and increased chromatin accessibility, respectively. Moreover, the impact of Tcf1, Blimp1, and Ahr alterations on the deregulated Trm differentiation in the absence of Bcl11b was confirmed by rescue experiments. In summary, we propose that Bcl11b promotes multipotency and restricts effector Trm programs, and is overall essential for small intestine Trm cell differentiation. This work was supported by grants from NIH (R01AI067846, R01AI133623) and Moffitt Cancer Center (P30CA076292).
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