INDUCTION OF ALLOANTIGEN-SPECIFIC TOLERANCE BY B-CELLS FROM CD40-DEFICIENT MICE

Interaction between CD40 on B cells and CD40 ligand molecules on T cel ls is pivotal for the generation of a thymus-dependent antibody respon se. Here ne show that B cells deficient in CD40 expression are unable to elicit the proliferation of allogeneic T cells in vitro. More impor tantly, mice immunized with CD40(-/-) B cells become tolerant to allog eneic major histocompatibility complex (MHC) antigens as measured by a mixed lymphocyte reaction and cytotoxic T-cell assay. The failure of CD40(-/-) B cells to serve as antigen presenting cells in vitro was co rrected by the addition of anti-CD28 mAb. Moreover, lipopolysaccharide stimulation, which upregulates B7 expression, reversed the inability of CD40(-/-) B cells to stimulate an alloresponse in vitro and abrogat ed the capacity of these B cells to induce tolerance in vivo. These re sults suggest that CD40 engagement by CD40 ligand expressed on antigen -activated T cells is critical for the upregulation of B7 molecules on antigen-presenting B cells that subsequently deliver the costimulator y signals necessary for T-cell proliferation and differentiation. Our experiments suggest a novel strategy for the induction of antigen-spec ific tolerance in vivo.