IMMUNE FUNCTIONS OF TUMOR-NECROSIS-FACTOR .1. TUMOR-NECROSIS-FACTOR INDUCES APOPTOSIS OF MOUSE THYMOCYTES AND CAN ALSO STIMULATE OR INHIBITIL-6-INDUCED PROLIFERATION DEPENDING ON THE CONCENTRATION OF MITOGENIC COSTIMULATION

Murine rTNF produces at least three effects on mouse thymocytes in vit ro: 1) Is a modest co-stimulator of proliferation with low PHA-P doses . 2) Has a bi-directional interaction with rIL-6 depending on PHA conc entration: at low PHA (5 to 10 mug/ml) TNF augments and at high PHA (2 0 to 30 mug/ml) inhibits IL-6-induced proliferation. A comparable bidi rectional PHA dose-dependent TNF interaction was seen with IL-1beta, w hereas only inhibition at high PHA with IL-2 and only augmentation at low PHA with IL-4 were seen. 3) TNF induces direct thymocyte apoptosis (a property not shared by IL-1beta, IL-2, IL-4, IL-6 and IL-7). Of th e cytokines studied, only IL-7 reduced TNF apoptosis. Thymocyte apopto sis by TNF showed the same species specificity as costimulation (i.e., human TNF had no effect) and was not inhibited by CY. The thymocyte C D4-CD8 phenotype after 72-h cultures showed that TNF decreased mainly double negative (DN) and single positive (SP) subsets, whereas IL-6 wi th low or high PHA increased DN and SP, especially the SP CD8+ subset. The regulatory and apoptotic effects of TNF were seen only with thymo cytes and not with peripheral splenic or lymph node T cells. Four mAb to mouse TNF (2E2, XT22, 1C6, and 1OD9) could abrogate TNF costimulati on and the TNF effects on IL-6-induced thymocyte proliferation, at bot h augmenting and inhibitory PHA conditions. However, only the two anti bodies that also neutralize TNF lytic activity (2E2, XT22) could inhib it TNF-mediated apoptosis, implying two different but neighboring func tional domains in the TNF molecule mediating apoptosis/lysis and costi mulation. Our studies show that TNF might have unique and complex regu latory effects on growth and death of thymocyte populations in adult m ice quite different from its effects on T cells in periphery.