Titration of CD45 expression regulates sequential tolerance checkpoints during B cell development (45.2)

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Abstract The receptor-like tyrosine phosphatase CD45 positively regulates antigen receptor (AgR) signaling by dephosphorylating the inhibitory tyrosine of the Src family kinases (SFKs). Here we take advantage of an allelic series of mice in which CD45 expression is titrated across a broad range (0-180%). Although high expression of CD45 inhibits TCR signaling, here we show that CD45 plays a purely positive regulatory role during BCR signaling. In concert with enhanced BCR signaling, mice expressing very high levels of CD45 exhibit marked loss of follicular and marginal zone B cells in a cell intrinsic manner. Although we do not see B cell loss at earlier stages of bone marrow development, we do find increasing lambda light chain usage across the CD45 allelic series suggesting that receptor editing is triggered by high CD45 expression. In the context of the IgHEL/sHEL model of B cell tolerance, such high CD45 expression transforms anergy into deletion. However, elimination of autoreactive ligand in this system fails to fully rescue survival of mature B cells in these mice. Indeed, we find that B cell survival upon exposure to BAFF is severely impaired by high CD45 expression, while low CD45 expression promotes response to BAFF. Titration of BAFF responsiveness by CD45 is cell intrinsic and correlates with BAFFR surface expression. This constitutes a novel mechanism by which B cells exhibiting hyper-responsive AgR signaling are kept in check during splenic B cell development.