Friday, November 22, 2024
11/22/2024
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.
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