Fc receptor-like 5 promotes B cell proliferation and drives the development of cells displaying switched isotypes

Abstract

The biological roles of B cell membrane proteins in the FCRL family are enigmatic. FCRL proteins, including FCRL5, were shown to modulate early BCR signaling, although the subsequent, functional consequences of receptor engagement are poorly understood. We found that FCRL5 surface protein itself was induced temporarily upon BCR stimulation of human, naive B cells, indicating precise control over timing of FCRL5 engagement. Cross-linking of FCRL5 on cells induced to express FCRL5 enhanced B cell proliferation significantly. This enhancement required costimulation of the BCR and TLR9, two signals required for optimal proliferation of naive B cells, whereas T cell help in the form of anti-CD40 and IL-2 was dispensable. In addition, we found that FCRL5 stimulation generated a high proportion of cells displaying surface IgG and IgA. Optimal development of cells expressing switched isotypes required T cell help, in addition to stimuli found necessary for enhanced proliferation. Surprisingly, cells that developed upon FCRL5 stimulation simultaneously displayed surface IgM, IgG, and IgA. Cells expressing multiple Ig isotypes were described in hairy cell leukemia, a disease in which FCRL5 is overexpressed. Enhanced proliferation and downstream isotype expression upon FCRL5 stimulation could reflect a physiological role for FCRL5 in the expansion and development of antigen-primed B cells. In addition, FCRL5 may promote growth of malignant cells in hairy cell leukemia and other FCRL5-expressing tumors.

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

“…We and others reported that FCRL5 binds intact IgG via a complex mechanism (21,22), and therefore immune complexes may link FCRL5 to the BCR, potentially blocking B cell activation similarly to the inhibitory FcgRIIB. Potential activating functions were also proposed for FCRL5 (23), similarly to FCRL3 (24) and FCRL4 (25), suggesting dual regulatory capacities. The expression level of FCRL5 is low in peripheral B cells, but it is increased in lymphoid tissues (14,16).…”

“…The poor in vitro response of the FCRL5 + TLM subset to a number of stimuli together with prominent expression of multiple inhibitory receptors suggests exhaustion, possibly in response to chronic Ag stimulus. FCRL5 expression itself could be a mark of previous BCR stimulation, as FCRL5 is specifically induced upon BCR stimulation (23). The type of Ag that drives TLM B cells in healthy individuals remains to be defined.…”

Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer

“…In humans, TLR9 is expressed primarily by plasmacytoid CD (pDC) and B cells [18–21]. Reflecting their utility as vaccine adjuvants, B lymphocytes exposed to TLR9 agonists become more susceptible to activation by Ag [22–24] while TLR9 stimulated pDC produce type I interferons and more efficiently present Ag to T cells [25–27]. Non-human primates (NHP) also respond to the same CpG motifs as humans.…”

Emerging Roles for the FCRL Family Members in Lymphocyte Biology and Disease

“…In a follow up analysis they investigated FCRL5 modulation following exposure to different stimuli and explored the consequences of its ligation on B cell responses. Although naïve B cells isolated from blood modestly upregulated protein levels when exposed to CpG, FCRL5 was markedly induced by anti-Ig co-stimulation (Dement-Brown et al, 2012). By contrast, the addition of T cell-dependent (TD) stimuli in the form of anti-CD40 and IL-2 had little effect.…”