FCRL1 in B cell differentiation - PROJECT SUMMARY
B lymphocytes are responsible for making antibodies in response to antigens from vaccination
and infection. Adaptive immunity involves activating and expanding B cells that can recognize
those antigens, produce neutralizing and opsonizing antibodies, and provide immunological
memory. The process by which this occurs involves a complex interplay of signals inside and
outside the cell to instruct B cells when to expand, modify their antigen receptor, and differentiate
into memory cells or antibody-secreting plasma cells. Much of this differentiation process occurs
in a specialized lymphoid structure called the germinal center. Our study seeks to understand
how B cells navigate the growth and differentiation process to optimize antibody responses. We
are studying a cell surface protein, FCRL1, found on all subsets of peripheral B cells. When the
B cell receptor (BCR) is engaged by antigen, FCRL1 enhances intracellular calcium signals while
suppressing the activation of ERK1/2. Mice deficient in FCRL1 have impaired antibody responses
and fewer germinal center B cells after immunization. We hypothesize that FCRL1 is controlling
B cell signals to maximize clonal expansion prior to differentiation. Using a model antigen system
and Fcrl1-/- mice, this study will track the kinetics of B cell activation and differentiation throughout
the germinal center response to the production of memory and plasma cells. It will examine how
FCRL1-mediated ERK inhibition alters B cell differentiation, and it will begin to uncover the
signaling pathway(s) used by FCRL1 to down-modulate BCR-induced ERK1/2 activation using
gene-targeted and transgenic B cell lines. This study will improve our understanding of signals
that provide optimal antibody responses to infection with the long-term aim of improving the
efficacy and durability of vaccines and immunotherapies.
