New programming of IL-4 receptor signal transduction in activated T cells: Stat6 induction and Th2 differentiation mediated by IL-4Ralpha lacking cytoplasmic tyrosines.
Signaling by the IL-4 receptor alpha-chain (IL-4Ralpha) is a key determinant of the development of the Th2 lineage of effector T cells. Studies performed in tissue culture cell lines have indicated that tyrosines of the IL-4Ralpha cytoplasmic tail are necessary for the induction of Stat6, a transcription factor required for Th2 differentiation. Surprisingly, we have found that in activated T cells, IL-4Ralpha chains lacking all cytoplasmic tyrosines promote induction of this IL-4-specific transcription factor and efficient commitment to the Th2 lineage. Mutagenesis of a tyrosine-free cytoplasmic tail identifies a requirement for the serine-rich ID-1 region in this new program of IL-4R signal transduction observed in activated T cells. Additional findings suggest that an extracellular signal-regulated kinase pathway can be necessary and sufficient for the ability of such tyrosine-free IL-4Ralpha chains to mediate Stat6 induction. These results provide novel evidence that the molecular mechanisms by which a cytokine specifically induces a Stat transcription factor can depend on the activation state of T lymphoid cells. Furthermore, the data suggest that one pathway by which such new programming may be achieved is mediated by extracellular signal-regulated mitogen-activated protein kinases.
Mora
Ana L
AL
Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Stephenson
Linda M
LM
Enerson
Ben
B
Youn
Jeehee
J
Keegan
Achsah D
AD
Boothby
Mark
M
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003593:Cytoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050800:STAT6 Transcription Factor; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000096:biosynthesis*; D014443:Tyrosine / Q000172:deficiency* / Q000235:genetics
D010446:Peptide Fragments; D021122:Protein Subunits; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014443:Tyrosine