We aim to better understand how B cell responses are regulated. The fate of B cells is dictated by the strength of the biochemical signaling that B cells receive through their antigen receptor (BCR), as well as through other receptors, such as CD40 and Toll-like receptors. Inhibitory feedback mechanisms play an important role in regulating the strength and duration of biochemical signals. In B cells these mechanisms are important to generate optimal antibody responses as well as to prevent the unwanted activation of B cells with irrelevant specificity and the potentially harmful activation of autoreactive B cells.
We primarily focus on the regulation of antigen receptor signaling. Many autoreactive B cells found in the periphery exist in a state of functional unresponsiveness, also called B cell anergy. In recent studies we found that BCR signaling is restricted in anergic B cells in two ways: by reducing the availability of antigen receptors and by active inhibitory signaling. This inhibitory signaling primarily involves the Lyn-SHIP-1-SHP-1 signaling axis and functions by restricting PI3K-dependent signaling. Currently we are working on identifying proteins/receptors involved in establishing and maintaining the Lyn-SHIP-1-SHP-1 signaling axis in autoreactive B cells by using a novel and unbiased discovery strategy. One of proteins we identified as interacting with SHIP-1 is CD79A (Ig alpha). CD79A is part of the CD79A/CD79B heterodimer that is associated with the B cell receptor and is required for the initiation of BCR signaling. Using newly generated CRISPR mutant mouse lines we are trying to identify how a protein with an essential activating function in B cells may also possess regulatory functions.
