Li Huifang, Borrego Francisco, Nagata Satoshi, Tolnay Mate
Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993;
Immunopathology Group, BioCruces Health Research Institute, 48903 Barakaldo, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain; and.
J Immunol. 2016 May 15;196(10):4064-74. doi: 10.4049/jimmunol.1501027. Epub 2016 Apr 13.
Fc receptor-like (FCRL) 5 is a novel IgG binding protein expressed on B cells, with the capacity to regulate Ag receptor signaling. We assessed FCRL5 expression on circulating B cells from healthy donors and found that FCRL5(+) cells are most enriched among atypical CD21(-/lo)/CD27(-) tissue-like memory (TLM) B cells, which are abnormally expanded in several autoimmune and infectious diseases. Using multicolor flow cytometry, FCRL5(+) TLM cells were found to express more CD11c and several inhibitory receptors than did the FCRL5(-) TLM subset. The homing receptor profiles of the two TLM subsets shared features consistent with migration away from lymphoid tissues, but they also displayed distinct differences. Analysis of IgH V regions in single cells indicated that although both subsets are diverse, the FCRL5(+) subset accumulated significantly more somatic mutations. Furthermore, the FCRL5(+) subset had more switched isotype expression and more extensive proliferative history. Microarray analysis and quantitative RT-PCR demonstrated that the two TLM subsets possess distinct gene expression profiles, characterized by markedly different CD11c, SOX5, T-bet, and RTN4R expression, as well as differences in expression of inhibitory receptors. Functional analysis revealed that the FCRL5(+) TLM subset responds poorly to multiple stimuli compared with the FCRL5(-) subset, as reflected by reduced calcium mobilization and blunted cell proliferation. We propose that the FCRL5(+) TLM subset, but not the FCRL5(-) TLM subset, underwent Ag-driven development and is severely dysfunctional. The present study elucidates the heterogeneity of TLM B cells and provides the basis to dissect their roles in the pathogenesis of inflammatory and infectious diseases.
Fc受体样（FCRL）5是一种在B细胞上表达的新型IgG结合蛋白，具有调节抗原受体信号传导的能力。我们评估了健康供体循环B细胞上的FCRL5表达，发现FCRL5（+）细胞在非典型CD21（- / lo）/ CD27（-）组织样记忆（TLM）B细胞中最为富集，这些细胞在几种自身免疫性和感染性疾病中异常扩增。使用多色流式细胞术，发现FCRL5（+）TLM细胞比FCRL5（-）TLM亚群表达更多的CD11c和几种抑制性受体。两个TLM亚群的归巢受体谱具有与远离淋巴组织迁移一致的特征，但它们也显示出明显的差异。单细胞中IgH V区的分析表明，虽然两个亚群都具有多样性，但FCRL5（+）亚群积累了明显更多的体细胞突变。此外，FCRL5（+）亚群具有更多的转换同种型表达和更广泛的增殖历史。微阵列分析和定量RT-PCR表明，两个TLM亚群具有不同的基因表达谱，其特征是CD11c、SOX5、T-bet和RTN4R表达明显不同，以及抑制性受体表达的差异。功能分析表明，与FCRL5（-）亚群相比，FCRL5（+）TLM亚群对多种刺激的反应较差，这表现为钙动员减少和细胞增殖减弱。我们提出，FCRL5（+）TLM亚群而非FCRL5（-）TLM亚群经历了抗原驱动的发育且严重功能失调。本研究阐明了TLM B细胞的异质性，并为剖析它们在炎症和感染性疾病发病机制中的作用提供了基础。
