Institute of Cell Genetics, Department for Genetics and Pharmacology, Medical University of Innsbruck, Peter Mayr Str. 1a, 6020 Innsbruck, Austria.
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Innrain 80, 6020 Innsbruck, Austria.
Cell Rep. 2019 Sep 10;28(11):2878-2891.e5. doi: 10.1016/j.celrep.2019.08.024.
CD4 T follicular helper (Tfh) cells are specialized in helping B cells during the germinal center (GC) reaction and ultimately promote long-term humoral immunity. Here we report that loss of the nuclear orphan receptor NR2F6 causes enhanced survival and accumulation of Tfh cells, GC B cells, and plasma cells (PCs) following T cell-dependent immunization. Nr2f6-deficient CD4 T cell dysfunction is the primary cause of cell accumulation. Cytokine expression in Nr2f6-deficient Tfh cells is dysregulated, and Il21 expression is enhanced. Mechanistically, NR2F6 binds directly to the interleukin 21 (IL-21) promoter and a conserved noncoding sequence (CNS) near the Il21 gene in resting CD4 T cells. During Tfh cell differentiation, this direct NR2F6 DNA interaction is abolished. Enhanced Tfh cell accumulation in Nr2f6-deficient mice can be reverted by blocking IL-21R signaling. Thus, NR2F6 is a critical negative regulator of IL-21 cytokine production in Tfh cells and prevents excessive Tfh cell accumulation.
CD4+滤泡辅助性 T 细胞（Tfh）在生发中心（GC）反应期间专门帮助 B 细胞，最终促进长期体液免疫。在这里，我们报告核孤儿受体 NR2F6 的缺失导致 T 细胞依赖性免疫接种后 Tfh 细胞、GC B 细胞和浆细胞（PC）的存活和积累增强。Nr2f6 缺陷型 CD4 T 细胞功能障碍是细胞积累的主要原因。Nr2f6 缺陷型 Tfh 细胞中的细胞因子表达失调，Il21 表达增强。在机制上，NR2F6 直接结合到静止 CD4 T 细胞中的白细胞介素 21（IL-21）启动子和 Il21 基因附近的保守非编码序列（CNS）上。在 Tfh 细胞分化期间，这种直接的 NR2F6 DNA 相互作用被废除。在 Nr2f6 缺陷型小鼠中，通过阻断 IL-21R 信号可以逆转增强的 Tfh 细胞积累。因此，NR2F6 是 Tfh 细胞中 IL-21 细胞因子产生的关键负调节剂，可防止 Tfh 细胞过度积累。
