Muthana Musleh M, Du Xuexiang, Liu Mingyue, Wang Xu, Wu Wei, Ai Chunxia, Su Lishan, Zheng Pan, Liu Yang
Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine; Baltimore, MD 21201, USA.
Department of Pharmacology, University of Maryland School of Medicine; Baltimore, MD 21201, USA.
bioRxiv. 2023 Aug 29:2023.03.01.530608. doi: 10.1101/2023.03.01.530608.
Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3 Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA-4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here we probe the decline of B cells in human CTLA-4 knock-in mice by using antihuman CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA-4 ADC). The anti-CTLA-4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF-alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.
生殖系CTLA-4缺陷会导致严重的自身免疫性疾病，其特征为Foxp3调节性T细胞（Tregs）失调、效应记忆T细胞过度活化以及包括B细胞逐渐丧失在内的多种形式的自身免疫性血细胞减少。接受抗CTLA-4/PD-1联合免疫治疗后出现严重免疫相关不良事件（irAE）的癌症患者外周血B细胞也显著减少。B细胞丧失的免疫学基础仍未得到解释。在此，我们通过使用与药物载荷恩杂鲁胺偶联的抗人CTLA-4抗体伊匹木单抗（抗CTLA-4 ADC）来探究人CTLA-4基因敲入小鼠中B细胞的减少情况。经抗CTLA-4 ADC处理的小鼠出现T细胞过度增殖并分化为效应细胞，从而导致B细胞耗竭。B细胞耗竭由CD4和CD8 T细胞介导，并且至少部分可通过抗TNF-α抗体挽救。这些数据揭示了T细胞和B细胞之间意想不到的拮抗作用以及调节性T细胞在保护B细胞中的重要性。
