A variety of tumors are potentially immunogenic but do not stimulate an effective anti-tumor immune response in vivo. Tumors may be capable of delivering antigen-specific signals to T cells, but may not deliver the costimulatory signals necessary for full activation of T cells. Expression of the costimulatory ligand B7 on melanoma cells was found to induce the rejection of a murine melanoma in vivo. This rejection was mediated by CD8+ T cells; CD4+ T cells were not required. These results suggest that B7 expression renders tumor cells capable of effective antigen presentation, leading to their eradication in vivo.

The recessive mouse mutations lpr and gld create deficiencies in an interacting pair of cell surface molecules, CD95 (Fas/APO-1) and Fas-ligand (FasL), respectively, resulting in autoantibody production resembling human systemic lupus erythematosus. The mechanisms of self-tolerance affected by deficiency in either molecule are not established, but CD95 deficiency both in B cells and in CD4+ T cells recognizing major histocompatibility complex (MHC) class II molecules is required for autoimmunity in lpr mice. Here we track the outcome of in vivo interactions between B cells and CD4+ T cells that recognize a transgene-encoded autoantigen, hen egg lysozyme (HEL), using cells from mice transgenic for immunoglobulin and T-cell receptor (TCR) genes. B cells that had not previously encountered HEL autoantigen (naive cells) were triggered into proliferation and antibody production upon interaction with antigen and HEL-specific CD4+ T cells. By contrast, B cells that had been chronically exposed to HEL during their development and carried desensitized surface immunoglobulin (sIg) antigen receptors (anergic cells) did not produce antibody but instead were eliminated in the presence of HEL-specific CD4+ T cells. CD95-deficient anergic B cells, however, were not eliminated by CD4+ T cells and were triggered to proliferate. These findings identify a novel regulatory step for eliminating autoreactive B cells that seems unique in its dependence on CD95.

Signals from CD4+ T cells induce two opposite fates in B cells: clonal proliferation of B cells that bind specifically to foreign antigens and clonal deletion of equivalent B cells that bind self-antigens. This B cell fate decision is determined by the concerted action of two surface proteins on activated T cells, CD40-and Fas-ligands (CD40L and FasL), whose effects are switched by signals from the B cell antigen receptor (BCR). Foreign antigens that stimulate the BCR acutely cause CD40L and FasL to promote clonal proliferation. CD40L and FasL trigger deletion, however, when the BCRs become desensitized by chronic stimulation with self-antigens or when BCRs have not bound an antigen. The need for both Fas and CD40L to correctly regulate self-reactive B cell fate may explain the severe autoantibody disorders in Fas- or CD40L-deficient children.