Switching on of the Proliferation or Apoptosis of Activated Human T Lymphocytes by IFN-γ Is Correlated with the Differential Expression of the α- and β-Chains of Its Receptor

To find out how physiologically secreted IFN-γ controls either the proliferation or the apoptosis of human T lymphocytes, the kinetics of expression of the α- and β-chains of its receptor (IFN-γR) were sequentially followed on T lymphocytes first activated with PHA and then cultured in the presence of IL-2, and related to the kinetics of expression of Fas, Bcl-2, and IL-2R p55 chain. Both IFN-γR chains were poorly expressed on the membrane of resting T lymphocytes. Following their stimulation with PHA, IFN-γRα but not IFN-γRβ-chain up-modulated before T lymphocyte entry into the S phase, and then IFN-γRα down-modulated when they passed through the S and G₂/M. The ensuing proliferative response was inhibited by an anti-IFN-γRα mAb that impeded the binding of IFN-γ. When PHA-activated T lymphoblasts were cultured for 16 days with IL-2, IFN-γRα expression increased, whereas that of the β-chain remained barely detectable. Fas and Bcl-2 were both highly expressed. When these T lymphoblasts were restimulated by PHA, OKT3, or Staphylococcus enterotoxin B-pokeweed mitogen, both chains up-modulated and most cells underwent apoptosis in a way apparently independent of Bcl-2, but not of Fas. This apoptosis, too, was prevented by the anti-IFN-γRα mAb. Physiologically secreted IFN-γ is thus involved in the activation of resting T lymphocytes and in the apoptosis of reactivated lymphoblasts. However, high expression of IFN-γRβ took place when IFN-γ induced apoptosis, but not when it induced proliferation. In conclusion, a correlation exists between differential expression of the IFN-γRβ-chain and the delivery by IFN-γ of proliferative or apoptotic signals.