Antigen-independent Th2 cell differentiation by stimulation of CD28: regulation via IL-4 gene expression and mitogen-activated protein kinase activation.
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 NH(2)-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.
Skapenko
A
A
Nikolaus Fiebiger Center for Molecular Medicine, Clinical Research Group III, University of Erlangen Nuremberg, Erlangen, Germany.
Lipsky
P E
PE
Kraetsch
H G
HG
Kalden
J R
JR
Schulze-Koops
H
H
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology; D018122:B7-1 Antigen / Q000378:metabolism / Q000502:physiology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004357:Drug Synergism; D004789:Enzyme Activation / Q000276:immunology; D005312:Fetal Blood; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D007399:Interphase / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D008024:Ligands; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D015847:Interleukin-4; D014443:Tyrosine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases