Induction of alloantigen-specific tolerance by B CELLS from CD40-defic1ent mice

Interaction between CD40 on B cells and CD40 ligand (CD40L) on T cells is pivotal for the generation of a thymusdependent antibody response. Here we show that B cells deficient in CD40 expression are unable to elicit the proliferation of alloantigen T cells in vitro. More importantly, mice immunized with CD40-/- B cells become tolerant to allogeneic major histocompatibility complex (MHC) antigens as measured by a mixed lymphocyte reaction (MLR) and cytotoxic T cell assay. The failure of CD40-/- B cells to serve as antigen, presenting cells (APCs) in vitro was corrected by the addition of ami-CD28 mAb. Moreover, lipopolysaccharide (LPS) stimulation, which upregulate B7 expression, reversed the inability of CD40-/- B cells to stimulate an alloresponse in vitro and abrogated the capacity of the B cells to induce tolerance in vivo. These results suggest that CD40 engagement by CD40 ligand expressed on antigen-activated T cells is critical for the upregulation of B7 molecules on antigenpresenting B cells which subsequently deliver the costimulatory signals necessary for T cell proliferation and differentiation. Our experiments suggest a novel strategy for the induction of antigenspecific tolerance in vivo.