Switching on of the proliferation or apoptosis of activated human T lymphocytes by IFN-gamma is correlated with the differential expression of the alpha- and beta-chains of its receptor.
To find out how physiologically secreted IFN-gamma controls either the proliferation or the apoptosis of human T lymphocytes, the kinetics of expression of the alpha- and beta-chains of its receptor (IFN-gamma R) 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-gamma R chains were poorly expressed on the membrane of resting T lymphocytes. Following their stimulation with PHA, IFN-gamma R alpha but not IFN gamma R beta-chain up-modulated before T lymphocyte entry into the S phase, and then IFN-gamma R alpha down-modulated when they passed through the S and G2/M. The ensuing proliferative response was inhibited by an anti-IFN-gamma R alpha mAb that impeded the binding of IFN-gamma. When PHA-activated T lymphoblasts were cultured for 16 days with IL-2, IFN-gamma R alpha expression increased, whereas that of the beta-chain remained barely detectable. Fas and Bcl-2 were both highly expressed. When these T lymphoblasts were restimulated by PHA, OKT3, or Staphylococcus enterotoxin beta-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-gamma R alpha mAb. Physiologically secreted IFN-gamma is thus involved in the activation of resting T lymphocytes and in the apoptosis of reactivated lymphoblasts. However, high expression of IFN-gamma R beta took place when IFN-gamma induced apoptosis, but not when it induced proliferation. In conclusion, a correlation exists between differential expression of the IFN-gamma R beta-chain and the delivery by IFN-gamma of proliferative or apoptotic signals.
Novelli
F
F
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
Bernabei
P
P
Ozmen
L
L
Rigamonti
L
L
Allione
A
A
Pestka
S
S
Garotta
G
G
Forni
G
G
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D004768:Enterotoxins / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011043:Pokeweed Mitogens / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000096:biosynthesis* / Q000737:chemistry; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D019014:fas Receptor / Q000096:biosynthesis; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D004768:Enterotoxins; D007371:Interferon-gamma; D007376:Interleukin-2; D010835:Phytohemagglutinins; D011043:Pokeweed Mitogens; D019253:Proto-Oncogene Proteins c-bcl-2; D017471:Receptors, Interferon; D015375:Receptors, Interleukin-2; D018089:Superantigens; D019014:fas Receptor; D000096743:Interferon gamma Receptor; C031818:enterotoxin B, staphylococcal