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The Journal of Immunology, 2001, 166: 4283-4292.
Copyright © 2001 by The American Association of Immunologists

Antigen-Independent Th2 Cell Differentiation by Stimulation of CD28: Regulation Via IL-4 Gene Expression and Mitogen-Activated Protein Kinase Activation1

Alla Skapenko*, Peter E. Lipsky{ddagger}, Hans-Georg Kraetsch{dagger}, Joachim R. Kalden{dagger} and Hendrik Schulze-Koops2,*,{dagger}

* Nikolaus Fiebiger Center for Molecular Medicine, Clinical Research Group III and {dagger} Department of Internal Medicine III and Institute for Clinical Immunology, Erlangen, Germany; and {ddagger} National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892

To delineate the molecular mechanisms regulating Th2 cell differentiation, CD28-mediated generation of Th2 effectors was analyzed. In the absence of TCR ligation CD28 stimulation induced Th2 differentiation of memory but not of naive CD4+ T cells, whereas costimulation via CD28 and the TCR enhanced Th2 differentiation from naive T cells but suppressed it from memory T cells. Stimulation of T cells via the CD28 pathway, therefore, provided critical signals facilitating Th2 cell differentiation. By comparing the responses to CD28 stimulation in memory and naive T cells and by using specific inhibitors, signaling pathways were defined that contributed to Th2 differentiation. CD28-induced Th2 differentiation required IL-4 stimulation and the activation of the mitogen-activated protein kinases p38 and extracellular signal-regulated kinases 1/2. CD28 engagement directly initiated IL-4 gene transcription in memory T cells and induced activation of phosphatidylinositol 3-kinase, p38, and c-Jun NH2-terminal kinase/stress-activated protein kinase pathways. Extracellular signal-regulated kinase phosphorylation that was necessary for Th2 differentiation, however, required stimulation by IL-2. These results indicate that optimal TCR-independent generation of Th2 effectors requires coordinate signaling via the CD28 and IL-2 pathways. TCR-independent generation of Th2 effectors might provide a mechanism to control Th1-dominated cellular inflammation.




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