初始 B 细胞和记忆 B 细胞分化为抗体分泌细胞 (ASC) 是适应性免疫的一个关键特征。磷酸肌醇 3-激酶-δ (PI3Kδ) 支持 B 细胞生物学的需求已得到深入研究；然而，B 谱系细胞中相关的磷酸肌醇 3-激酶-γ (PI3Kγ) 复合物的特定功能却没有。在本研究中，我们报告 PI3Kγ 促进 T 细胞依赖性抗原诱导的强烈抗体反应。由于人类缺乏 PI3Kγ 引起的先天性免疫缺陷会导致广泛的体液缺陷，这促使我们研究该激酶在抗体反应中的作用。使用小鼠免疫模型，我们发现 PI3Kγ 以激酶活性依赖性方式在激活的 B 细胞内本质上发挥细胞功能，以转导支持 ASC 分化的转录程序所需的信号。此外，ASC 的命运选择与 PIK3CG 表达的上调一致，并且在体外 CD40/细胞因子驱动激活的初始 B 细胞、Toll 样受体激活的记忆 B 细胞或人扁桃体中 PI3Kγ 破坏的情况下受到损害。类器官。总而言之，我们的研究揭示了 PI3Kγ 通过整合指示对 ASC 命运的承诺的信号来支持体液免疫的基本作用。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.