Mukta Deobagkar-Lele, Greg Crawford, Tanya L. Crockford, Jennifer Back, Rose Hodgson, Aneesha Bhandari, Katherine R. Bull, Richard J. Cornall
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引用次数: 0
Abstract
Dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome is characterized by a failure of the germinal center response, a process involving the proliferation and positive selection of antigen-specific B cells. Here, we describe how DOCK8-deficient B cells are blocked at a light-zone checkpoint in the germinal centers of immunized mice, where they are unable to respond to T cell–dependent survival and selection signals and consequently differentiate into plasma cells or memory B cells. Although DOCK8-deficient B cells can acquire and present antigen to initiate activation of cognate T cells, integrin up-regulation, B cell–T cell conjugate formation, and costimulation are insufficient for sustained B cell and T cell activation when antigen availability is limited. Our findings provide an explanation for the failure of the humoral response in DOCK8 immunodeficiency syndrome and insight into how the level of available antigen modulates B cell–T cell cross-talk to fine-tune humoral immune responses and immunological memory.
细胞因子发生器 8(DOCK8)免疫缺陷综合征的特征是生殖中心反应失败,这一过程涉及抗原特异性 B 细胞的增殖和阳性选择。在这里,我们描述了 DOCK8 缺失的 B 细胞如何在免疫小鼠生殖中心的光区检查点受阻,无法对 T 细胞依赖的存活和选择信号做出反应,从而分化成浆细胞或记忆 B 细胞。虽然 DOCK8 缺失的 B 细胞可以获取并呈现抗原以启动同源 T 细胞的活化,但当抗原供应有限时,整合素上调、B 细胞-T 细胞结合体形成和成本刺激不足以实现 B 细胞和 T 细胞的持续活化。我们的研究结果解释了 DOCK8 免疫缺陷综合征中体液反应失败的原因,并深入探讨了可用抗原水平如何调节 B 细胞-T 细胞交叉对话,以微调体液免疫反应和免疫记忆。
期刊介绍:
Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.