ILA, A MEMBER OF THE HUMAN NERVE GROWTH-FACTOR TUMOR-NECROSIS-FACTOR RECEPTOR FAMILY, REGULATES T-LYMPHOCYTE PROLIFERATION AND SURVIVAL

ILA, a gene induced by lymphocyte activation, is a member of the human nerve growth factor tumor necrosis factor receptor family and the hum an homologue of murine 4-1BB. The present study analyzed the role of I LA in the regulation of human peripheral blood T-lymphocyte function. Antibodies raised against different fusion proteins recognized ILA on activated lymphocytes. These antibodies significantly increased anti-C D3-induced T-lymphocyte proliferation. When anti-CD3-stimulated cells were incubated on ILA-expressing CHO cells, proliferation was inhibite d. CHO cells transfected with a control construct and not expressing I LA did not reduce T-cell proliferation. A purified fusion protein cont aining the extracellular domain of ILA and the constant domain of huma n IgG (ILA-IgG) also inhibited lymphocyte proliferation. Results obtai ned by H-3-thymidine incorporation were confirmed by cell cycle analys is that showed a decrease in the number of lymphocytes in S phase. Lym phocyte morphology in cultures with ILA-expressing CHO cells was sugge stive of apoptosis. Flow cytometry on propidium iodide-stained cells s howed a time-dependent increase in the number of hypodiploid apoptotic cells when lymphocytes were cultured on ILA-expressing CHO cells. Int ernucleosomal DNA cleavage was seen in these cultures, but not in the presence of ILA-negative CHO cells. Studies on the mechanism by which ILA regulates T-cell function showed that ILA-IgG inhibited anti-CD3-i nduced T-cell proliferation when presented in immobilized but not in s oluble form. These results suggest that ILA may act by cross-linking i ts ligand and thereby inhibit T-cell proliferation. (C) 1996 by The Am erican Society of Hematology.