B7-BLOCKING AGENTS, ALONE OR IN COMBINATION WITH CYCLOSPORINE-A, INDUCE ANTIGEN-SPECIFIC ANERGY OF HUMAN-MEMORY T-CELLS

T cell anergy refers to a functional state in which the cells are aliv e but unable to produce IL-2 after appropriate triggering. Lack of CD2 8 costimulation through CD80 and CD86 molecules on APC might play a ca usative role in anergy induction, as previously shown with T cell clon es. We now developed a model of anergy induction in cultures of freshl y isolated memory T cells. Addition of either CTLA-4Ig or blocking ant i-CD80 and anti-CD86 mAbs, in combination with cyclosporin A, to cultu res of PBMC with soluble Ag consistently resulted in Ag-specific unres ponsiveness, as evidenced upon antigenic rechallenge. In most experime nts, the presence of cyclosporin A was not required, and blocking the B7-CD28 interaction during antigenic stimulation was sufficient to ind uce unresponsiveness. Unresponsiveness was apparent at the level of T cell proliferation as well as at the level of IL-2 and IFN-gamma produ ction, and T cell responses to unrelated Ags were intact. Induction of unresponsiveness correlated with lack of T cell proliferation in the induction culture and could largely be prevented by supplementing the induction cultures with rlL-2, indicating that lack of IL-2 was respon sible for this altered functional state. Unresponsive T cells did not suppress the proliferation of autologous T cells in response to origin al or third-party Ags. On the other hand, culture with IL-2 and Ag cou ld reverse established T cell unresponsiveness, pointing to anergy rat her than deletion as the underlying mechanism. Anergy induction in fre shly isolated memory T cells opens perspectives for treatment of autoi mmune and allergic diseases.