ANTIBODIES TO TR2 (HERPESVIRUS ENTRY MEDIATOR), A NEW MEMBER OF THE TNF RECEPTOR SUPERFAMILY, BLOCK T-CELL PROLIFERATION, EXPRESSION OF ACTIVATION MARKERS, AND PRODUCTION OF CYTOKINES

TR2 (TNFR-related 2) is a recently identified member of the TNFR famil y with homology to TNFRII. We have demonstrated previously that TR2 mR NA is expressed in resting and activated human T cells and that TR2-Ig partially inhibits an allogeneic mixed leukocyte proliferation respon se. We now characterize TR2 further by the use of specific mAbs, Flow- cytometry analysis using TR2 mAbs confirmed that resting PBL express h igh levels of cell surface TR2, and that TR2 is widely expressed on al l freshly isolated lymphocyte subpopulations. However, stimulation of purified T cells with either PHA or PHA plus PMA resulted in decreased surface expression within 48 h of activation before returning to rest ing levels at 72 h. TR2 mAbs inhibited CD4(+) T cell proliferation in response to stimulation by immobilized CD3 or CD3 plus CD28 mAbs, Assa y of culture supernatants by ELISA showed inhibition of TNF-alpha, IFN -gamma, IL-2, and IL-4 production, which, for IL-2 and TNF-alpha was a lso confirmed by intracellular cytokine staining. Furthermore, express ion of activation markers on CD4(+) T cells, including CD25, CD30, CD6 9, CD71, and OX40 (CD134), was inhibited. TR2 mAbs inhibited prolifera tion in a three-way MLR, and a response to soluble recall Ag, tetanus toroid. In conclusion, these results suggest that TR2 is involved in t he activation cascade of T cell responses and TR2 mAbs prevent optimal T cell proliferation, cytokine production, and expression of activati on markers.