Section of Transplantation, Department of Surgery, University of Chicago, Chicago, Illinois, USA.
School of Medicine, Indiana University, Indianapolis, Indiana, USA.
J Clin Invest. 2020 Jul 1;130(7):3453-3466. doi: 10.1172/JCI132814.
The absence of alloantibodies is a feature of transplantation tolerance. Although the lack of T cell help has been evoked to explain this absence, herein we provide evidence for B cell-intrinsic tolerance mechanisms. Using a murine model of heart tolerance, we showed that alloreactive B cells were not deleted but rapidly lost their ability to differentiate into germinal center B cells and secrete donor-specific antibodies. We inferred that tolerant alloreactive B cells retained their ability to sense alloantigen because they continued to drive T cell maturation into CXCR5+PD-1+ T follicular helper cells. Unexpectedly, dysfunctional alloreactive B cells acquired the ability to inhibit antibody production by new naive B cells in an antigen-specific manner. Thus, tolerant alloreactive B cells contribute to transplantation tolerance by foregoing germinal center responses while retaining their ability to function as antigen-presenting cells and by actively suppressing de novo alloreactive B cell responses.
同种异体抗体的缺失是移植耐受的一个特征。尽管缺乏 T 细胞的帮助被认为是导致这种缺失的原因，但在这里我们提供了 B 细胞内在耐受机制的证据。使用心脏耐受的小鼠模型，我们表明同种反应性 B 细胞并未被删除，而是迅速失去了分化为生发中心 B 细胞并分泌供体特异性抗体的能力。我们推断，耐受的同种反应性 B 细胞保留了识别同种抗原的能力，因为它们继续驱动 T 细胞成熟为 CXCR5+PD-1+滤泡辅助 T 细胞。出乎意料的是，功能失调的同种反应性 B 细胞获得了以抗原特异性方式抑制新的幼稚 B 细胞产生抗体的能力。因此，耐受的同种反应性 B 细胞通过放弃生发中心反应而保留其作为抗原呈递细胞的功能，并通过积极抑制新的同种反应性 B 细胞反应，为移植耐受做出贡献。
