Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai, China; Shanghai Institute of Immunology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai, China.
Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, Guangdong, China; The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou 510632, Guangdong, China.
Cell Immunol. 2024 Nov-Dec;405-406:104883. doi: 10.1016/j.cellimm.2024.104883. Epub 2024 Oct 18.
CD11c age-associated B cells (ABCs) have emerged as a key component in protective and autoreactive B cell responses. Lupus is an autoimmune disorder linked to reduced efficacy of vaccines and increased susceptibility to infections. Previously, we reported that excessive CD11c ABCs not only significantly contribute to autoantibody production but also promote aberrant T cell activation and compromised affinity-based germinal center selection in response to immunization in lupus mice. Yet, the regulation of CD11c ABC differentiation is not fully understood. In this study, we show that B cell-intrinsic IFN-γ is required for excessive CD11c ABC differentiation in lupus mice. B cell-intrinsic IFN-γ is mainly produced by CD11c ABCs. IFN-γ-deficiency leads to decreased expression of ABC characteristic genes. We further show that ablating IFN-γ can normalize T cell overactivation and rescue antigen-specific GC responses in lupus mice. Our study offers insight into the crucial role of B cell-intrinsic IFN-γ in promoting excessive CD11c ABC differentiation, which compromises affinity-based germinal center selection and affinity maturation in lupus, providing a potential strategy to normalize vaccine responses in lupus.
CD11c 年龄相关 B 细胞（ABCs）已成为保护性和自身反应性 B 细胞反应的关键组成部分。狼疮是一种自身免疫性疾病，与疫苗效力降低和感染易感性增加有关。先前，我们报道称，过多的 CD11c ABC 不仅显著促进自身抗体的产生，而且在狼疮小鼠的免疫反应中促进异常的 T 细胞激活和基于亲和力的生发中心选择受损。然而，CD11c ABC 分化的调节尚未完全了解。在这项研究中，我们表明，固有 IFN-γ是狼疮小鼠中过多 CD11c ABC 分化所必需的。固有 IFN-γ主要由 CD11c ABC 产生。IFN-γ 缺陷导致 ABC 特征基因表达减少。我们进一步表明，消除 IFN-γ可以使狼疮小鼠中的 T 细胞过度激活正常化，并挽救抗原特异性 GC 反应。我们的研究深入了解了固有 IFN-γ在促进过多 CD11c ABC 分化中的关键作用，该作用损害了狼疮中的亲和力为基础的生发中心选择和亲和力成熟，为在狼疮中使疫苗反应正常化提供了一种潜在策略。
