title: Fc Receptor-like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue-like Memory B Cells.
abstract: 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.
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Huifang
authors.identifier: 0000-0001-5701-1518
authors.initials: H
authors.lastname: Li
authors.affiliation: Immunopathology Group, BioCruces Health Research Institute, 48903 Barakaldo, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain; and.
authors.forename: Francisco
authors.initials: F
authors.lastname: Borrego
authors.affiliation: Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Satoshi
authors.identifier: 0000-0001-9156-5215
authors.initials: S
authors.lastname: Nagata
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993; mate.tolnay@fda.hhs.gov.
authors.forename: Mate
authors.initials: M
authors.lastname: Tolnay
mesh_terms: D001327:Autoimmune Diseases / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001773:Blood Cells / Q000276:immunology*; D020013:Calcium Signaling; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D006801:Humans; D017578:Immunoglobulin Class Switching; D007156:Immunologic Memory; D007239:Infections / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: C432367:FCRL5 protein, human; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc