The proposed research will investigate a newly discovered T-cell costimulatory pathway defined by the MRC OX-2 protein. Recent experiments have supported the hypothesis that T-cell costimulatory signals represent an important physiologic and therapeutic control point for the modification of T-cell mediated immune responses. As such responses have been demonstrated to be central to mechanisms involved in autoimmunity, tumor biology and transplantation, their study impacts directly on medically relevant issues. One extensively studied costimulatory pathway, the B7/CD28 pathway, delivers its signal when a receptor on T-cells, called CD28, is engaged by either of two ligands, B7-1 or B7-2, expressed on antigen presenting cells. A literature search for additional B7-like proteins identified OX-2, a rat lymphocyte activation marker, as a promising candidate gene. Despite the failure of OX-2 to bind the B7 receptors, CD28 and CTLA4, it can stimulate T-cell proliferation. In addition, this proliferation occurs in the apparent absence of IL-2, IL-4 or IFN-gamma. Further, interest in OX-2 has recently emerged from the finding that human herpes virus 8 (HHV8) as well as other herpes viruses, encode OX-2 homologues. HHV8 has been implicated in Kaposi s sarcoma, multiple myeloma, Castleman's Disease, and primary effusion lymphoma. Herpes virus encoded genes have been documented to modulate lymphocyte migration and antigen presentation. A viral OX-2 homologue suggests that T-cell costimulatory signals have also been targeted. Thus OX-2 acts through a non B7/CD28 pathway leading to functionally distinct consequences as reflected in the resulting cytokine profile. The objective of this research is to elucidate the physiologic role of the OX-2 costimulatory pathway and to determine its relationship to the well-studied B7/CD28 costimulatory pathway. The proposed studies will be carried out using techniques that have effectively employed in related experiments on the B7/CD28 pathway.
The first aim seeks to use established molecular biology approach to determine the spatial and temporal pattern of OX-2 expression while the second aim seeks to use cellular biology techniques to ascertain how and on which cell types OX-2 exerts its proliferative effect. These studies are likely to illuminate the role of the OX-2 costimulatory pathway in vitro and establish the theoretical foundation with which to carry out further studies on the role of this pathway in vivo.
