Yang Jinghui, Chen Jianjun, Young James S, Wang Qiang, Yin Dengping, Sciammas Roger, Chong Anita S
1 Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.2 Department of Organ Transplantation, Shanghai ChangZheng Hospital, Second Military Medical University, Shanghai, China.3 Center for Immunobiology and Transplant Research, Department of Surgery, The Houston Methodist Hospital Research Institute, Houston, TX.
Transplantation. 2016 Aug;100(8):1683-91. doi: 10.1097/TP.0000000000001253.
The dual role of B cells as drivers and suppressors of the immune responses have underscored the need to trace the fate of B cells recognizing donor major histocompatibility complex class I and class II after allograft transplantation.
In this study, we used donor class II tetramers to trace the fate of I-E-specific B cells after immunization with BALB/c spleen cells or cardiac transplantation, in naive or sensitized C57BL/6 recipients. We combined this approach with genetic lineage tracing of memory B cells in activation-induced cytidine deaminase regulated Cre transgenic mice crossed to the ROSA26-enhanced yellow fluorescent protein reporter mice to track endogenous I-E-specific memory B cell generation.
Immunization with BALB/c splenocytes or heart transplantation induced an expansion and differentiation of I-E-specific B cells into germinal center B cells, whereas BALB/c heart transplantation into sensitized recipients induced the preferential differentiation into antibody-secreting cells. A 10.8-fold increase in the frequency of I-E-specific memory B cells was observed by day 42 postimmunization. Treatment with CTLA4-Ig starting on day 0 or day 7 postimmunization abrogated I-E-specific memory B cell generation and sensitized humoral responses, but not if treatment commenced on day 14.
The majority of donor-specific memory B cells are generated between days 7 and 14 postimmunization, thus revealing a flexible timeframe whereby delayed CTLA4-Ig administration can inhibit sensitization and the generation of memory graft-reactive B cells.
B细胞在免疫反应中兼具驱动和抑制作用，这凸显了追踪同种异体移植后识别供体主要组织相容性复合体I类和II类的B细胞命运的必要性。
在本研究中，我们使用供体II类四聚体来追踪在初次免疫或致敏的C57BL/6受体中，用BALB/c脾细胞免疫或进行心脏移植后，I-E特异性B细胞的命运。我们将这种方法与激活诱导的胞苷脱氨酶调控的Cre转基因小鼠与ROSA26增强型黄色荧光蛋白报告小鼠杂交后的记忆B细胞遗传谱系追踪相结合，以追踪内源性I-E特异性记忆B细胞的产生。
用BALB/c脾细胞免疫或心脏移植诱导I-E特异性B细胞扩增并分化为生发中心B细胞，而将BALB/c心脏移植到致敏受体中则诱导其优先分化为抗体分泌细胞。免疫后第42天观察到I-E特异性记忆B细胞频率增加了10.8倍。在免疫后第0天或第7天开始用CTLA4-Ig治疗可消除I-E特异性记忆B细胞的产生并使体液反应致敏，但在第14天开始治疗则不会。
大多数供体特异性记忆B细胞在免疫后第7天至14天之间产生，从而揭示了一个灵活的时间框架，在此期间延迟给予CTLA4-Ig可抑制致敏和记忆性移植物反应性B细胞的产生。
