CTL generation in the presence of IL-4 is inhibited by free p40: evidence for early and late IL-12 function.
The cytokine requirements for the generation of a CTL response were examined using thymocyte responders stimulated with Con A. In agreement with previous reports, IL-4 alone can generate a strong CTL response. To determine whether IL-12 was required for this response, we added either a neutralizing Ab against IL-12 or an antagonist of IL-12 function, p40. Both anti-IL-12 and p40 were found to inhibit the generation of CTL in the presence of IL-4. Consistent with these data, exogenous IL-12 was found to synergize with IL-4, particularly, when IL-4 was added at levels unable to generate a CTL response alone. This synergistic response was observed whether IL-12 was added at the beginning of culture along with IL-4 or after the first day to cultures initiated with IL-4. Likewise, the combination of IL-2 plus IL-12 evoked a strong synergistic response when cultures were initiated with IL-2 and IL-12 was added initially or after the first day of culture. Addition of either IL-2 or IL-12 alone did not generate a response. In contrast to these data showing that IL-12 was able to signal late in culture, p40 inhibited CTL generation in response to IL-4 only when added at the beginning of culture. These results imply that CTL induction involves a crucial early IL-12 signal, which once delivered permits cells to respond to a later IL-12 signal. These data are consistent with the idea that free circulating p40 could inhibit the generation of CTL by antagonizing the early IL-12 "differentiation" signal.
Abdi
K
K
Genetics Institute, Inc., Cambridge, MA 02140, USA. KAbdi@Genetics.com
Herrmann
S H
SH
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology* / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000906:Antibodies; D016207:Cytokines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D018664:Interleukin-12; D015847:Interleukin-4