Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8+ T cells.
Eric Y Helm, Tomas Zelenka, Valeriu B Cismasiu, Shamima Islam, Leonardo Silvane, Beatrice Zitti, Tim D Holmes, Theodore T Drashansky, Alexander J Kwiatkowski, Christine Tao, Joseph Dean, Alyssa N Obermayer, Xianghong Chen, Benjamin G Keselowsky, Weizhou Zhang, Zhiguang Huo, Liang Zhou, Brian S Sheridan, Jose R Conejo-Garcia, Timothy I Shaw, Yenan T Bryceson, Dorina Avram
Science immunology 2023 Apr 28The networks of transcription factors (TFs) that control intestinal-resident memory CD8+ T (TRM) cells, including multipotency and effector programs, are poorly understood. In this work, we investigated the role of the TF Bcl11b in TRM cells during infection with Listeria monocytogenes using mice with post-activation, conditional deletion of Bcl11b in CD8+ T cells. Conditional deletion of Bcl11b resulted in increased numbers of intestinal TRM cells and their precursors as well as decreased splenic effector and circulating memory cells and precursors. Loss of circulating memory cells was in part due to increased intestinal homing of Bcl11b-/- circulating precursors, with no major alterations in their programs. Bcl11b-/- TRM cells had altered transcriptional programs, with diminished expression of multipotent/multifunctional (MP/MF) program genes, including Tcf7, and up-regulation of the effector program genes, including Prdm1. Bcl11b also limits the expression of Ahr, another TF with a role in intestinal CD8+ TRM cell differentiation. Deregulation of TRM programs translated into a poor recall response despite TRM cell accumulation in the intestine. Reduced expression of MP/MF program genes in Bcl11b-/- TRM cells was linked to decreased chromatin accessibility and a reduction in activating histone marks at these loci. In contrast, the effector program genes displayed increased activating epigenetic status. These findings demonstrate that Bcl11b is a frontrunner in the tissue residency program of intestinal memory cells upstream of Tcf1 and Blimp1, promoting multipotency and restricting the effector program.
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Eric Y Helm, Tomas Zelenka, Valeriu B Cismasiu, Shamima Islam, Leonardo Silvane, Beatrice Zitti, Tim D Holmes, Theodore T Drashansky, Alexander J Kwiatkowski, Christine Tao, Joseph Dean, Alyssa N Obermayer, Xianghong Chen, Benjamin G Keselowsky, Weizhou Zhang, Zhiguang Huo, Liang Zhou, Brian S Sheridan, Jose R Conejo-Garcia, Timothy I Shaw, Yenan T Bryceson, Dorina Avram. Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8+ T cells. Science immunology. 2023 Apr 28;8(82):eabn0484
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PMID: 37115913
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