MODULATION OF INTERFERON-GAMMA RECEPTOR DURING HUMAN T-LYMPHOCYTE ALLOACTIVATION

Previous work has shown that neutralization of physiologically secrete d interferon(IFN)-gamma or blockade of its receptor during T lymphocyt e activation inhibits both proliferation and cytotoxic T lymphocyte ge neration, suggesting that IFN-gamma plays a crucial role in T lymphocy te induction and differentiation. In this study, the kinetics of the s urface expression of the 90-kDa IFN-gamma receptor (IFN-gammaR) was fo llowed during human mixed lymphocyte reaction (MLR) to alloantigens. I FN-gammaR mRNA is constitutively expressed on resting peripheral blood lymphocytes emerging from nylon wood column (NW-PBL) and its expressi on increases two- to threefold on alloactivated NW-PBL. IFN-gammaR pro tein is poorly expressed on the membrane of resting CD3+ cells, but up -modulates after 3-day MLR and sharply down-modulates at day 6. Both t he p55 and the p75 chains of interleukin-2 receptor (IL-2R) were shown to up-modulate in parallel with IFN-gammaR, whereas they were still h ighly expressed at day 6. After alloactivation, EFN-gamma and IL-2 sec retion starts at 24 h, peaks at day 3 and decreases just when IFN-gamm aR and IL-2R begin to up-modulate. Proliferation peaks at day 6. Lastl y, stimulation with distinct cell populations showed that the intensit y of lymphocyte proliferation, IFN-gammaR membrane up-modulation, and IFN-gamma and IL-2 secretion are regulated in a parallel manner, thus suggesting that they are interrelated. Taken as whole these results de monstrate that increased expression of IFN-gammaR on T lymphocytes can be a critical event during their activation, and strongly support the hypothesis that IFN-gamma/IFN-gammaR interaction provides a signal fo r its progression.