CD21 and FCRL5 form a receptor complex with robust B-cell activating capacity

Abstract

The B-cell response to antigen is critically regulated by co-receptors. CD21 (complement receptor 2) amplifies the response to antigen linked to its ligands, specific C3 fragments. In contrast, human Fc receptor-like 5 (FCRL5), a novel IgG receptor, was reported to inhibit B-cell receptor (BCR) signaling. Here, we show that CD21 and FCRL5 physically associate, suggesting that immune complexes containing both C3 fragment and IgG could simultaneously engage the pre-assembled receptors. We found that activating signaling molecules such as CD19, active PLCγ2 and BTK were rapidly recruited to FCRL5 upon engagement, suggesting a novel activating function for FCRL5. We confirmed that FCRL5 through its ITIMs (immunoreceptor tyrosine-based inhibitory motif) inhibited BCR signaling in the absence of CD21 stimulation. In contrast, triple engagement of FCRL5, CD21 and the BCR led to a superior calcium response compared to CD21 and BCR co-stimulation, in both cell lines and tonsil B cells. Furthermore, the novel activating function was independent of established FCRL5 signaling motifs. While human peripheral B cells express either FCRL5 or CD21, we identified a sizable subset of tonsil B cells which co-express the two receptors. We propose that FCRL5 has dual signaling capacity, while CD21 co-engagement serves as molecular switch, converting FCRL5 from a negative to a positive co-receptor. In tissues, B cells that co-express FCRL5 and CD21 could robustly respond to IgG immune complexes loaded with C3 fragments.

FCRL5+ Memory B Cells Exhibit Robust Recall Responses

“…The mouse gene Fcrl5 possesses significant sequence and domain homology to both human FCRL5 and human FCRL3, whereas its cellular expression patterns resemble those of human FCRL3 ( Li et al, 2014 ). FCRL5 is known to be expressed in murine B-1 cells and human B-1 and B-2 cells and may play either an activating or an inhibitory role depending on its context ( Franco et al, 2018 ; Li et al, 2014 ; Rakhmanov et al, 2009 ; Zhu et al, 2013 ). Yet, little is known about FCRL5 expression and function in murine B-2 cells.…”

The Ligands for Human IgG and Their Effector Functions

“…Both receptors are found on B cells suggesting a role in regulation of humoral immune responses [76]. One recent study suggested that FcRL5 can induce either inhibiting or activating signals to B cell receptor signaling pathways, depending on coligation with complement receptor 2 (CD21) [77]. This seems to suggest that complement C3 deposition may convert an inherent inhibitory signal to an activating signal and positively stimulate the humoral immune response.…”

A close-up on the expanding landscape of CD21–/low B cells in humans

“…Indeed, signalling via FcRL4 in the context of BCR activation is inhibitory; however, in the context of Toll-like receptor (TLR) agonists it is activating [ 83 ]. Like FcRL4, FcRL5 is a member of the Fc receptor-like proteins and has immunomodulatory potential [ 84 ], and is also expressed on CD21–/low MBCs in HIV [ 20 ]. Unlike FcRL4, which is a receptor for IgA, FcRL5 binds IgG [ 85 ].…”