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

Abstract

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 a 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 a cells was reduced 3- to 4-fold compared to Btk(M) mice and mature B cells (IgM(low)/IgD(high)) were virtually absent; serum levels of all Ig isotypes were diminished; and antibody responses to TI-I, TI-II and thymus-dependent antigens were impaired. Furthermore, although wild-type Btk(M) and CD40(M) mice produced germinal centers in response to TI-I antigen, the Btk(M)CD40(M) mice did not. Maturational and functional B 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.