Reciprocal regulation of B cell antigen receptor signaling by CD148 and Csk
- Author(s): Skrzypczynska, Katarzyna Maria
- Advisor(s): Weiss, Arthur
- et al.
B cell antigen receptor (BCR) signaling is tightly regulated by the opposing actions of receptor-like protein tyrosine phosphatases (RPTPs) and C-terminal Src kinase (Csk). The RPTPs CD45 and CD148 positively regulate BCR signaling through their actions on Src-family kinases (SFKs) and have redundant functions in conventional (B2) B cell signaling and activation. However, we found that IgM production in response to T cell-independent type 2 antigens, which is mediated in large part by B1 B cells, was deficient in mice lacking CD148. B1 B cells, which normally express high levels of CD148 compared with B2 B cells, were uniquely affected by the loss of CD148, resulting in impaired proliferation, antibody production, BCR repertoire development, and BCR signaling. Analysis of proximal BCR signaling in mice deficient in CD148 or the SFK Lyn revealed that Lyn has a predominantly positive regulatory role in B1 B cell BCR signaling, compared with its dominant negative regulatory role observed in B2 B cells. This suggests that BCR signaling circuitry is wired differently in B1 B cells resulting in a requirement for positive regulation of Lyn by CD148 for full BCR signaling. Using novel tools recently generated in the lab, we also investigated the effects of selective chemical inhibition of Csk in primary mouse follicular B cells. This preliminary work reveals mechanisms for the negative regulation of BCR signaling by Csk independent of BCR engagement.