Ogishi Masato, Kitaoka Koji, Good-Jacobson Kim L, Rinchai Darawan, Zhang Baihao, Wang Jun, Gies Vincent, Rao Geetha, Nguyen Tina, Avery Danielle T, Khan Taushif, Smithmyer Megan E, Mackie Joseph, Yang Rui, Arias Andrés Augusto, Asano Takaki, Ponsin Khoren, Chaldebas Matthieu, Zhang Peng, Peel Jessica N, Bohlen Jonathan, Lévy Romain, Pelham Simon J, Lei Wei-Te, Han Ji Eun, Fagniez Iris, Chrabieh Maya, Laine Candice, Langlais David, Gruber Conor, Al Ali Fatima, Rahman Mahbuba, Aytekin Caner, Benson Basilin, Dufort Matthew J, Domingo-Vila Clara, Moriya Kunihiko, Shlomchik Mark, Uzel Gulbu, Gray Paul E, Suan Daniel, Preece Kahn, Chua Ignatius, Okada Satoshi, Chikuma Shunsuke, Kiyonari Hiroshi, Tree Timothy I, Bogunovic Dusan, Gros Philippe, Marr Nico, Speake Cate, Oram Richard A, Béziat Vivien, Bustamante Jacinta, Abel Laurent, Boisson Bertrand, Korganow Anne-Sophie, Ma Cindy S, Johnson Matthew B, Chamoto Kenji, Boisson-Dupuis Stéphanie, Honjo Tasuku, Casanova Jean-Laurent, Tangye Stuart G
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; The David Rockefeller Graduate Program, Rockefeller University, New York, NY 10065, USA.
Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan.
Immunity. 2024 Dec 10;57(12):2790-2807.e15. doi: 10.1016/j.immuni.2024.10.014. Epub 2024 Nov 26.
T follicular helper (Tfh) cells abundantly express the immunoreceptor programmed cell death protein 1 (PD-1), and the impact of PD-1 deficiency on antibody (Ab)-mediated immunity in mice is associated with compromised Tfh cell functions. Here, we revisited the role of the PD-1-PD-L1 axis on Ab-mediated immunity. Individuals with inherited PD-1 or PD-L1 deficiency had fewer memory B cells and impaired Ab responses, similar to Pdcd1 and Cd274Pdcd1lg2 mice. PD-1, PD-L1, or both could be detected on the surface of human naive B cells following in vitro activation. PD-1- or PD-L1-deficient B cells had reduced expression of the transcriptional regulator c-Myc and c-Myc-target genes in vivo, and PD-1 deficiency or neutralization of PD-1 or PD-L1 impeded c-Myc expression and Ab production in human B cells isolated in vitro. Furthermore, B cell-specific deletion of Pdcd1 prevented the physiological accumulation of memory B cells in mice. Thus, PD-1 shapes optimal B cell memory and Ab-mediated immunity through B cell-intrinsic and B cell-extrinsic mechanisms, suggesting that B cell dysregulation contributes to infectious and autoimmune complications following anti-PD-1-PD-L1 immunotherapy.
滤泡辅助性T（Tfh）细胞大量表达免疫受体程序性细胞死亡蛋白1（PD-1），PD-1缺陷对小鼠抗体（Ab）介导免疫的影响与Tfh细胞功能受损有关。在此，我们重新探讨了PD-1-PD-L1轴在Ab介导免疫中的作用。与Pdcd1和Cd274Pdcd1lg2小鼠相似，患有遗传性PD-1或PD-L1缺陷的个体记忆B细胞较少且抗体反应受损。体外激活后人幼稚B细胞表面可检测到PD-1、PD-L1或两者。体内PD-1或PD-L1缺陷的B细胞转录调节因子c-Myc及其靶基因的表达降低，体外分离的人B细胞中，PD-1缺陷或PD-1或PD-L1的中和会阻碍c-Myc表达和抗体产生。此外，B细胞特异性缺失Pdcd1可阻止小鼠记忆B细胞的生理性积累。因此，PD-1通过B细胞内在和外在机制塑造最佳的B细胞记忆和Ab介导的免疫，提示B细胞失调导致抗PD-1-PD-L1免疫治疗后的感染和自身免疫并发症。
