MRC OX-2 DEFINES A NOVEL T-CELL COSTIMULATORY PATHWAY

T cell activation requires the engagement of the TCR as well as a seco nd, costimulatory signal. In this study, we demonstrate that MRC OX-2 (OX-2) mediates a previously unrecognized T cell costimulatory signal leading to enhanced T cell proliferation. One extensively studied cost imulatory pathway, the B7/CD28 pathway, delivers its signal when CD28 is engaged by either of two ligands, B7-1 or B7-2, expressed on APC. R ecent data have suggested that an additional ligand may exist in this pathway, This possibility prompted us to search previously cloned gene s with both structural and expression characteristics similar to B7-1 and B7-2. Our search yielded OX-2, a rat lymphocyte activation marker, as a promising candidate gene, We now report that Chinese hamster ova ry cell transfectants expressing the OX-2 protein can costimulate muri ne CD4(+) T cells to proliferate in an Ag-independent fashion using an ti-CD3, as well as an Ag-dependent fashion using peptide, In contrast to B7-1-mediated costimulation, OX-2 does not result in detectable lev els of IL-2, IL-4, or IFN-gamma. In addition, OX-2 transfectants do no t bind the soluble receptor reagents of the B7/CD28 pathway (CD28-Ig a nd CTLA4Ig). Furthermore, OX-2 costimulation is not inhibited by CTLA4 Ig, as is B7-1-mediated costimulation, but is readily inhibited with a n anti-OX-2 mAb, Thus, OX-2 is a T cell costimulatory ligand that acts through a non-B7/CD28 pathway, which leads to functionally distinct c onsequences, as reflected by the resulting cytokine profile.