Uncoupling IL-2 production from apoptosis and TNF production by changing the signal through the TCR.
T cells may discriminate between stimuli in a variety of ways, including the presence of cytokines or other costimulatory signals, the type of Ag (peptide, superantigen, or allorecognition), or the magnitude of the signal through the TCR. We have used anti-CD3 stimulation of T hybridomas to examine signals generated through the TCR in the absence of exogenous APCs. Soluble whole anti-CD3, but not F(ab')2 anti-CD3, was able to stimulate the T hybridomas to produce IL-2. Plastic-bound anti-CD3, in contrast, stimulated TNF production, G1 arrest, and apoptosis by the T hybridoma. Engagement of the CD4 coreceptor on these cells had no effect on the overall pattern of signaling observed. Although TNF production was correlated with apoptosis, anti-TNF treatment did not prevent cell death or G1 arrest. The response of the T hybridoma to both forms of anti-CD3 included significant IL-2 production even at the lowest dose tested. However, soluble anti-CD3 at the highest dose tested elicited only minor apoptosis, while plastic-bound anti-CD3 elicited significant apoptosis even at the lowest dose. The difference in response was not evident at the level of phosphotyrosine proteins two min after cross-linking of the TCR.
Glickstein
L
L
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York 10021.
Macphail
S
S
Stutman
O
O
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D006825:Hybridomas; D007376:Interleukin-2 / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases