Fc Receptor-like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue-like Memory B Cells

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.

MeSH terms

  • Autoimmune Diseases / immunology*
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocytes / immunology*
  • Blood Cells / immunology*
  • Calcium Signaling
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • DNA Mutational Analysis
  • Gene Expression Regulation
  • Humans
  • Immunoglobulin Class Switching
  • Immunologic Memory
  • Infections / immunology*
  • Receptors, Antigen, B-Cell / metabolism*
  • Receptors, Fc / genetics
  • Receptors, Fc / metabolism*
  • Tissue Array Analysis


  • FCRL5 protein, human
  • Receptors, Antigen, B-Cell
  • Receptors, Fc