IL-4-responsive human helper T cell clones are resistant to growth inhibition by tumor necrosis factor-alpha.
Positive and negative signals for clonal expansion of preactivated human CD4+ alloreactive Th cells have been examined. Fifteen T cell clones tested 3 days after Ag-specific stimulation proliferated with IL-2 but only five of these responded to IL-4. The remaining 10 also failed to respond to IL-4 in the presence of IL-1 and/or autologous B-LCL. The response of the latter five to IL-4 was independent of IL-2 as shown by the inability of IL-2R mAb to prevent proliferation. In contrast, transferrin R mAb blocked responses to both IL-2 and IL-4. IL-4 responder but not nonresponder clones demonstrated IL-4-enhanced responses to suboptimal concentrations of IL-2 (1 U/ml), but none of the clones showed enhanced responses with 1 U/ml IL-2 plus IL-1, IL-3, IL-5, or granulocyte-macrophage-CSF. IFN-gamma did not enhance or inhibit responses to either IL-2 or IL-4. TNF-alpha did not block proliferation supported by IL-4. In contrast, TNF-alpha did block proliferative responses to IL-2, but only by those clones which were incapable of responding to IL-4. Thus, proliferation of the IL-4-responder clones was not blocked by TNF-alpha when optimal or even supraoptimal concentrations of IL-2 were used as growth factor. Because all T cell clones themselves secreted TNF-alpha after specific stimulation, these results suggest a novel autocrine negative regulatory pathway, whereby IL-4-reactive helper cells would have a selective advantage over IL-4-nonreactive cells during the evolution of an immune response.
Pawelec
G P
GP
Second Department of Internal Medicine, University Medical Clinic, Tübingen, Federal Republic of Germany.
Rehbein
A
A
Schaudt
K
K
Busch
F W
FW
D002454:Cell Differentiation / Q000187:drug effects; D002999:Clone Cells / Q000276:immunology / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4; D007378:Interleukins / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4