Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing, China.
Sci Immunol. 2018 Nov 30;3(29). doi: 10.1126/sciimmunol.aau6598.
Protective antibody responses to vaccination or infection depend on affinity maturation, a process by which high-affinity germinal center (GC) B cells are selected on the basis of their ability to bind, gather, and present antigen to T follicular helper (T) cells. Here, we show that human GC B cells have intrinsically higher-affinity thresholds for both B cell antigen receptor (BCR) signaling and antigen gathering as compared with naïve B cells and that these functions are mediated by distinct cellular structures and pathways that ultimately lead to antigen affinity- and T cell-dependent differentiation to plasma cells. GC B cells bound antigen through highly dynamic, actin- and ezrin-rich pod-like structures that concentrated BCRs. The behavior of these structures was dictated by the intrinsic antigen affinity thresholds of GC B cells. Low-affinity antigens triggered continuous engagement and disengagement of membrane-associated antigens, whereas high-affinity antigens induced stable synapse formation. The pod-like structures also mediated affinity-dependent antigen internalization by unconventional pathways distinct from those of naïve B cells. Thus, intrinsic properties of human GC B cells set thresholds for affinity selection.
保护性抗体应答依赖于疫苗接种或感染引起的亲和力成熟，这是一个基于其结合、聚集和呈递抗原给滤泡辅助性 T 细胞（Tfh）的能力选择高亲和力生发中心（GC）B 细胞的过程。在这里，我们发现与初始 B 细胞相比，人类 GC B 细胞的 B 细胞抗原受体（BCR）信号和抗原聚集的固有亲和力阈值更高，并且这些功能由不同的细胞结构和途径介导，最终导致抗原亲和力和 T 细胞依赖性向浆细胞分化。GC B 细胞通过富含肌动蛋白和 ezrin 的高动态、足状样结构结合抗原，这些结构将 BCR 集中在一起。这些结构的行为取决于 GC B 细胞的固有抗原亲和力阈值。低亲和力抗原触发膜相关抗原的连续结合和脱离，而高亲和力抗原诱导稳定的突触形成。足状样结构还通过与初始 B 细胞不同的非典型途径介导依赖亲和力的抗原内化。因此，人类 GC B 细胞的固有特性为亲和力选择设定了阈值。
