EXPRESSION AND FUNCTION OF THE COSTIMULATORY MOLECULE B7 ON MURINE LANGERHANS CELLS - EVIDENCE FOR AN ALTERNATIVE CTLA-4 LIGAND

We have previously shown, through transfection experiments, that the m urine B7 (mB7) molecule, a ligand for the CD28 and CTLA-4 receptors, i s a sufficient costimulatory signal for the antigen-specific and major histocompatibility complex (MHC)-restricted activation of murine CD4( +) T lymphocytes. In addition to mB7, another ligand with affinity for CTLA-4 has been described on spleen cells. Here we report our studies on the expression and function of these molecules on murine Langerhan s cells (LC). Both anti-mB7 monoclonal antibody (mAb) 16-10A1 and huma n CTLA4Ig (hCTLA4Ig), a chimeric fusion protein consisting of the extr acellular domain of human CLTA-4 and the constant domain of human IgG1 , detected antigens(s) on cultured but not freshly isolated LC. Preinc ubation of cultured LC with anti-mB7 mAb did not significantly affect binding of hCTLA4Ig to these cells. This result demonstrate the existe nce of at least one other ligand for the CLTA-4 receptor on cultured L C. Functional studies revealed that the costimulatory activity of LC w as inhibited better by hCTLA4Ig than by the anti-mB7 mAb. This differe ntial effect was seen in the case of both alloreactive and antigen-spe cific, syngeneic T cell responses. These findings suggest that the non -mB7-ligand for CTLA-4 is functional and participates in the induction of immune responses by LC. Importantly, even synergistic combinations of anti-mB7 mAb and hCTLA4Ig did not inhibit completely the activity of LC. These findings therefore raise the possibility that LC express other costimulatory ligands besides mB7 and related family members.