美国耶鲁大学医学院Carrie L. Lucas团队近期取得重要工作进展，他们研究提出，B细胞中的PI3Kγ促进抗体反应和抗体分泌细胞的产生。相关研究成果2024年7月3日在线发表于《自然—免疫学》杂志上。

据介绍，初始和记忆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，相关的磷酸肌醇3-激酶-γ（PI3Kγ）复合物在B谱系细胞中的特异性功能还不清楚。

研究人员报道了PI3Kγ促进T细胞依赖性抗原诱导的强大抗体反应。由人类PI3Kγ缺乏引起的先天性免疫错误导致广泛的体液缺陷，促使研究人员对这种激酶在抗体反应中的作用进行深入探讨。使用小鼠免疫模型，研究人员发现PI3Kγ以激酶活性依赖的方式在活化的B细胞内固有地发挥细胞功能，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表达的上调相一致，并且在体外CD40/细胞因子驱动的活化的naive B细胞、toll样受体活化的记忆B细胞或人类扁桃体类器官中的PI3Kγ破坏的背景下受损。

总之，这一研究揭示了PI3Kγ通过整合指示ASC命运的信号来支持体液免疫的基本作用。

附：英文原文

Title: PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells

Author: Lanahan, Stephen M., Yang, Lucas, Jones, Kate M., Qi, Zhihong, Cabrera, Emylette Cruz, Cominsky, Lauren Y., Ramaswamy, Anjali, Barmada, Anis, Gabernet, Gisela, Uthaya Kumar, Dinesh Babu, Xu, Lan, Shan, Peiying, Wymann, Matthias P., Kleinstein, Steven H., Rao, V. Koneti, Mustillo, Peter, Romberg, Neil, Abraham, Roshini S., Lucas, Carrie L.

Issue&Volume: 2024-07-03

Abstract: 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.

DOI: 10.1038/s41590-024-01890-1

Source: https://www.nature.com/articles/s41590-024-01890-1