Montreal Clinical Research Institute, Montreal, Quebec, Canada.
Department of Microbiology and Immunology, Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada.
J Exp Med. 2020 Sep 7;217(9). doi: 10.1084/jem.20191537.
Antigen uptake and presentation by naive and germinal center (GC) B cells are different, with the former expressing even low-affinity BCRs efficiently capture and present sufficient antigen to T cells, whereas the latter do so more efficiently after acquiring high-affinity BCRs. We show here that antigen uptake and processing by naive but not GC B cells depend on Cbl and Cbl-b (Cbls), which consequently control naive B and cognate T follicular helper (Tfh) cell interaction and initiation of the GC reaction. Cbls mediate CD79A and CD79B ubiquitination, which is required for BCR-mediated antigen endocytosis and postendocytic sorting to lysosomes, respectively. Blockade of CD79A or CD79B ubiquitination or Cbls ligase activity is sufficient to impede BCR-mediated antigen processing and GC development. Thus, Cbls act at the entry checkpoint of the GC reaction by promoting naive B cell antigen presentation. This regulation may facilitate recruitment of naive B cells with a low-affinity BCR into GCs to initiate the process of affinity maturation.
抗原摄取和呈递在初始 B 细胞和生发中心（GC）B 细胞中有所不同，前者即使表达低亲和力 BCR 也能有效地捕获和呈递足够的抗原给 T 细胞，而后者在获得高亲和力 BCR 后更有效地进行抗原摄取和呈递。我们在这里表明，抗原摄取和加工在初始 B 细胞中起作用，但在 GC B 细胞中不起作用，这取决于 Cbl 和 Cbl-b（Cbls），它们因此控制着初始 B 细胞和同源滤泡辅助 T（Tfh）细胞的相互作用以及 GC 反应的启动。Cbls 介导 CD79A 和 CD79B 的泛素化，这分别是 BCR 介导的抗原内吞作用和内吞后分拣到溶酶体所必需的。阻断 CD79A 或 CD79B 的泛素化或 Cbls 连接酶活性足以阻碍 BCR 介导的抗原加工和 GC 的发育。因此，Cbls 通过促进初始 B 细胞抗原呈递，在 GC 反应的入口检查点发挥作用。这种调节可能有助于招募具有低亲和力 BCR 的初始 B 细胞进入 GC 以启动亲和力成熟过程。
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