Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells.
Antigen-presenting cells (APC) tailor immune responses to microbial encounters by stimulating differentiation of CD4 T cells into the Th1 and Th2 lineages. We demonstrate that APC use the Notch pathway to instruct T cell differentiation. Strikingly, of the two Notch ligand families, Delta induces Th1, while Jagged induces the alternate Th2 fate. Expression of these different Notch ligands on APC is induced by Th1- or Th2-promoting stimuli. Th2 differentiation has been considered a default process as APC-derived instructive signals are unknown. We demonstrate that Jagged constitutes an instructive signal for Th2 differentiation, which is independent of IL4/STAT6. Th2 differentiation induced by APC is abrogated in T cells lacking the Notch effector RBPJkappa. Notch directs Th2 differentiation by inducing GATA3 and by directly regulating il4 gene transcription through RBPJkappa sites in a 3' enhancer.
Amsen
Derk
D
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Blander
J Magarian
JM
Lee
Gap Ryol
GR
Tanigaki
Kenji
K
Honjo
Tasuku
T
Flavell
Richard A
RA
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology*; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000276:immunology; D050990:GATA3 Transcription Factor; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4 / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000276:immunology; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000276:immunology*; D000072099:Serrate-Jagged Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D015534:Trans-Activators / Q000276:immunology; D014157:Transcription Factors
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C064045:delta protein; D015847:Interleukin-4