DEFECTIVE B-CELL DEVELOPMENT AND FUNCTION IN BTK-DEFICIENT MICE

Mutations in the Bruton's tyrosine kinase (Btk) gene have been linked to severe early B cell developmental blocks in human X-linked agammagl obulinemia (XLA), and to milder B cell activation deficiencies in muri ne X-linked immune deficiency (Xid). To elucidate unequivocally potent ial Btk functions in mice, we generated mutations in embryonic stem ce lls, which eliminated the ability to encode Btk pleckstrin homology or kinase domains, and assayed their effects by RAG2-deficient blastocys t complementation or introduction into the germline. Both mutations bl ock expression of Btk protein and lead to reduced numbers of mature co nventional B cells, severe B1 cell deficiency, serum IgM and lgG3 defi ciency, and defective responses in vitro to various B cell activators and in vivo to immunization with thymus-independent type II antigens. These results prove that lack of Btk function results in an Xid phenot ype and further suggest a differential requirement for Btk during the early stages of murine versus human B lymphocyte development.