Impaired B cell maturation in mice lacking Bruton's tyrosine kinase (Btk) and CD40

Mutations in Bruton's tyrosine kinase (Btk) gene, in mice, result in reduced numbers and responses of peripheral B cells, Surface Ig-mediated signaling is defective in Btk mutant B cells as they do not proliferate upon sig cross-linking and lack thymus-independent (TI) type II responses, Signals through sig and CD40 play a critical role in B cell maturation, To investigate the consequences of the lack of both Btk and CD40 on B cell development and function, mice were generated that were homozygous for targeted mutations in the Btk and the CD40 genes (Btk(M)CD40(M)), The CD40 mutation (CD40(M)) had a synergistic effect on the Btk(M) defects, In Btk(M)CD40(M) mice the number of B cells was reduced 3- to 4-fold compared to Bfk(M) mice and mature a cells (IgW(low)/IgD(high)) were virtually absent; serum levels of all Ig isotypes were diminished; and antibody responses to TI-I, TI-ll and thymus-dependent antigens were impaired, Furthermore, although wild-type Btk(M) and CD40(M) mice produced germinal centers in response to TI-l antigen, the Bfk(M)CD40(M) mice did not, Maturational and functional a cell defects in Btk(M)CD40(M) mice may result from a combination of intrinsic B cell defects, lack of CD40L-dependent T cell help and microenvironmental defects, These data suggest that signals through Btk and CD40 are necessary for the production and maintenance of the mature B cell.