STIMULATION OF HUMAN T-CELL PROLIFERATION BY SPECIFIC ACTIVATION OF THE 75-KDA TUMOR-NECROSIS-FACTOR RECEPTOR

TNF-alpha can enhance the proliferation of human thymocytes stimulated by the comitogen Con A. To determine which of the two different TNF r eceptors is responsible for signaling this cellular response, we inves tigated the proliferation of human thymocytes in response to agonistic antibodies specific for the two TNF receptor types. In contrast to pr eviously examined TNF activities in human cells, thymocyte proliferati on was stimulated in response to rabbit polyclonal antibodies directed against the 75-kDa TNF receptor (TNF-R2), but not those directed agai nst the 55-kDa TNF receptor (TNF-R1). Lymphotoxin (TNF-beta) was also shown to stimulate human thymocyte proliferation, demonstrating that T NF-beta can initiate a biologic response that is mediated by TNF-R2. T NF-R2-mediated T-cell proliferation was not restricted to the immature T cells within the thymus, as the anti-TNF-R2 antibodies also stimula ted the proliferation of peripheral T cells. As a first step toward id entifying a specific agonist of TNF-R2 with therapeutic potential, 10 anti-TNF-R2 mAb were examined for potential agonist activity. Nine of these significantly stimulated human thymocyte proliferation with maxi mal responses ranging from twofold to significantly greater than that obtained with TNF-alpha by itself.