Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan.
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan; Chiba University Synergy Institute for Futuristic Mucosal Vaccine Research and Development (cSIMVa), Chiba, Japan.
Biochem Biophys Res Commun. 2023 Jul 5;664:9-19. doi: 10.1016/j.bbrc.2023.04.065. Epub 2023 Apr 22.
T follicular regulatory (Tfr) cells, a subset of CD4 Foxp3 regulatory T (Treg) cells, locate to the lymphoid follicle and germinal center (GC) and regulate antibody responses. Tfr cells express the functional molecules of follicular helper T (Tfh) cells, including CXCR5 and Bcl6. CD25 mature Tfr cells differentiate from CD25 Treg cells through CD25 immature Tfr cells. Others and we have shown that Achaete-scute complex homolog 2 (Ascl2) plays a role in Tfh cell development; however, the role of Ascl2 in the development of Tfr cells remains unclear. Here, we found that Ascl2 was highly and preferentially expressed in CD25 Tfr cells and CD25 Tfr cells, and that the differentiation from CD25 Tfr cells to CD25 Tfr cells was impaired by the absence of Ascl2. Furthermore, the forced Ascl2 expression in Treg cells downregulated CD25 expression and suppressed IL-2-induced phosphorylation of STAT5, which is known to suppress CD25 Tfr cell development. Finally, we found that the downregulation of CD25 by Ascl2 in Treg cells is independent of Bach2, which also regulates CD25 downregulation in CD25 Tfr cells. These results suggest that Ascl2 plays a vital role in developing Tfr cells, possibly by downregulating CD25 expression in a Bach2-independent mechanism.
滤泡辅助性 T（Tfh）细胞是滤泡辅助性 T（Tfh）细胞的一个亚群，位于淋巴滤泡和生发中心（GC），调节抗体反应。Tfr 细胞表达滤泡辅助性 T（Tfh）细胞的功能性分子，包括 CXCR5 和 Bcl6。CD25 成熟 Tfr 细胞通过 CD25 不成熟 Tfr 细胞从 CD25 Treg 细胞分化而来。其他人，包括我们，已经表明 Achaete-scute 复合物同源物 2（Ascl2）在 Tfh 细胞发育中发挥作用；然而，Ascl2 在 Tfr 细胞发育中的作用尚不清楚。在这里，我们发现 Ascl2 在 CD25 Tfr 细胞和 CD25 Tfr 细胞中高度且优先表达，并且 Ascl2 的缺失会损害 CD25 Tfr 细胞的分化。此外，在 Treg 细胞中强制表达 Ascl2 会下调 CD25 的表达，并抑制已知抑制 CD25 Tfr 细胞发育的 IL-2 诱导的 STAT5 磷酸化。最后，我们发现 Ascl2 在 Treg 细胞中下调 CD25 的表达与 Bach2 无关，Bach2 也调节 CD25 Tfr 细胞中 CD25 的下调。这些结果表明 Ascl2 在 Tfr 细胞的发育中起着至关重要的作用，可能通过 Bach2 独立的机制下调 CD25 的表达。
