Dept of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
Dept of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
Cell. 2021 Apr 1;184(7):1775-1789.e19. doi: 10.1016/j.cell.2021.02.027. Epub 2021 Mar 11.
Regulatory T cells prevent the emergence of autoantibodies and excessive IgE, but the precise mechanisms are unclear. Here, we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) cells, produce abundant neuritin protein that targets B cells. Mice lacking Tfr cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased plasma IgE and IgG1. We show that neuritin is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching. Neuritin reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1, and upregulated BCL6. Administration of neuritin to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of neuritin by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies.
调节性 T 细胞可防止自身抗体和 IgE 过度产生，但确切的机制尚不清楚。在这里，我们表明表达 BCL6 的 T 调节细胞（Tfr 细胞）会产生大量神经丝蛋白，该蛋白靶向 B 细胞。缺乏 Tfr 细胞或 Foxp3 表达细胞中神经丝蛋白的小鼠，生发中心（GC）中早期浆细胞积累，并产生针对组蛋白和组织特异性自身抗原的自身抗体。在免疫接种后，这些小鼠还产生了更多的血浆 IgE 和 IgG1。我们表明神经丝蛋白被 B 细胞摄取，导致许多蛋白质发生磷酸化，并抑制 IgE 类别转换。神经丝蛋白可减少小鼠和人类 GC B 细胞向浆细胞的分化，下调 BLIMP-1 并上调 BCL6。向 Tfr 细胞缺陷小鼠给予神经丝蛋白可防止 GC 中早期浆细胞的积累。Tfr 细胞产生神经丝蛋白是抑制 B 细胞驱动的自身免疫和 IgE 介导的过敏反应的核心机制。
