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

Area of Science:

• Immunology
• Cell Biology

Background:

• B-cell activation is regulated by co-receptors like CD21 and Fc receptor-like 5 (FCRL5).
• CD21 amplifies responses to C3 fragments, while FCRL5 was previously thought to inhibit B-cell receptor (BCR) signaling.

Purpose of the Study:

• To investigate the interaction and signaling interplay between CD21 and FCRL5 in B cells.
• To elucidate the dual signaling capacity of FCRL5 and its regulation by CD21.

Main Methods:

• Co-immunoprecipitation to assess physical association between CD21 and FCRL5.
• Analysis of signaling molecule recruitment (CD19, PLCγ2, BTK) to FCRL5 upon stimulation.
• Calcium flux assays to measure B-cell activation upon co-engagement of BCR, CD21, and FCRL5.
• Flow cytometry to identify B-cell subsets co-expressing FCRL5 and CD21.

Main Results:

• CD21 and FCRL5 physically associate, enabling simultaneous engagement by immune complexes.
• FCRL5 recruits activating signaling molecules (CD19, PLCγ2, BTK) upon engagement, indicating a novel activating function.
• FCRL5 inhibits BCR signaling alone via its ITIMs, but co-engagement with CD21 and BCR leads to superior calcium responses.
• This activating function is independent of known FCRL5 signaling motifs.
• A subset of tonsil B cells co-expresses FCRL5 and CD21.

Conclusions:

• FCRL5 possesses dual signaling capacity, acting as an inhibitory co-receptor or an activating co-receptor.
• CD21 acts as a molecular switch, converting FCRL5 from an inhibitor to an activator.
• Co-expression of FCRL5 and CD21 in specific B-cell populations allows for robust responses to IgG- and C3-fragment-containing immune complexes.