BTK DOSAGE DETERMINES SENSITIVITY TO B-CELL ANTIGEN RECEPTOR CROSS-LINKING

Mutations in Btk result in the B cell immunodeficiencies X-linked agam maglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Btk is a critical component of signaling pathways regulating B c ell development and function. We used a genetic approach to determine whether Btk is also limiting for these processes. One allele of a muri ne Btk transgene expressed a dosage of Btk (25% of endogenous levels i n splenic B cells) sufficient to restore normal numbers of phenotypica lly mature conventional B cells in rid mice. 2,3,6-trinitrophenyl-Fico ll response, anti-IgM-induced proliferation, B1 cell development, and serum IgM and IgG(3) levels remained significantly impaired in these a nimals. B cells from Btk -/- transgenic mice also responded poorly to anti-IgM, indicating that the xid mutation does not create a dominant negative form of Btk Response to 2,4,6-trinitrophenyl-Ficoll and B cel l receptor cross-linking were increased 3- to 4-fold in rid mice homoz ygous for the transgene. These results demonstrate that Btk is a limit ing component of B cell antigen receptor signaling pathways and sugges t that B cell development and response to antigen may require differen t levels of Btk activity.