Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston MA 02115, USA.
Sci Immunol. 2018 Sep 14;3(27). doi: 10.1126/sciimmunol.aat5861.
Foxp3CD4 regulatory T cells (T) accumulate in certain nonlymphoid tissues, where they control diverse aspects of organ homeostasis. Populations of tissue T, as they have been termed, have transcriptomes distinct from those of their counterparts in lymphoid organs and other nonlymphoid tissues. We examined the diversification of T in visceral adipose tissue, skeletal muscle, and the colon vis-à-vis lymphoid organs from the same individuals. The unique transcriptomes of the various tissue T populations resulted from layering of tissue-restricted open chromatin regions over regions already open in the spleen, the latter tagged by super-enhancers and particular histone marks. The binding motifs for a small number of transcription factor (TF) families were repeatedly enriched within the accessible chromatin stretches of T in the three nonlymphoid tissues. However, a bioinformatically and experimentally validated transcriptional network, constructed by integrating chromatin accessibility and single-cell transcriptomic data, predicted reliance on different TF family members in the different tissues. The network analysis also revealed that tissue-restricted and broadly acting TFs were integrated into feed-forward loops to enforce tissue-specific gene expression in nonlymphoid-tissue T. Overall, this study provides a framework for understanding the epigenetic dynamics of T cells operating in nonlymphoid tissues, which should inform strategies for specifically targeting them.
Foxp3+CD4 调节性 T 细胞（T 细胞）在某些非淋巴组织中聚集，在那里它们控制着器官内环境的各个方面。这些组织 T 细胞，正如它们被命名的那样，其转录组与淋巴器官和其他非淋巴组织中的对应物不同。我们研究了内脏脂肪组织、骨骼肌和结肠中 T 细胞的多样化，以及来自同一个体的淋巴器官。各种组织 T 细胞群体的独特转录组是由于组织受限的开放染色质区域叠加在脾脏中已经开放的区域上形成的，后者被超级增强子和特定的组蛋白标记标记。在三个非淋巴组织中 T 细胞的可及染色质区域内，少数转录因子（TF）家族的结合基序被反复富集。然而，通过整合染色质可及性和单细胞转录组学数据构建的生物信息学和实验验证的转录网络预测，不同组织中对不同 TF 家族成员的依赖。网络分析还表明，组织受限和广泛作用的 TF 被整合到前馈回路中，以在非淋巴组织 T 细胞中强制表达组织特异性基因。总的来说，这项研究为理解在非淋巴组织中发挥作用的 T 细胞的表观遗传动力学提供了一个框架，这应该为有针对性地靶向它们的策略提供信息。
