An instructive component in T helper cell type 2 (Th2) development mediated by GATA-3.
Although interleukin (IL)-12 and IL-4 polarize naive CD4(+) T cells toward T helper cell type 1 (Th1) or Th2 phenotypes, it is not known whether cytokines instruct the developmental fate in uncommitted progenitors or select for outgrowth of cells that have stochastically committed to a particular fate. To distinguish these instructive and selective models, we used surface affinity matrix technology to isolate committed progenitors based on cytokine secretion phenotype and developed retroviral-based tagging approaches to directly monitor individual progenitor fate decisions at the clonal and population levels. We observe IL-4-dependent redirection of phenotype in cells that have already committed to a non-IL-4-producing fate, inconsistent with predictions of the selective model. Further, retroviral tagging of naive progenitors with the Th2-specific transcription factor GATA-3 provided direct evidence for instructive differentiation, and no evidence for the selective outgrowth of cells committed to either the Th1 or Th2 fate. These data would seem to exclude selection as an exclusive mechanism in Th1/Th2 differentiation, and support an instructive model of cytokine-driven transcriptional programming of cell fate decisions.
Department of Pathology and Center for Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
J D
JD
Farrar
W
W
Ouyang
M
M
Löhning
M
M
Assenmacher
A
A
Radbruch
O
O
Kanagawa
K M
KM
Murphy
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002455:Cell Division; D002460:Cell Line; D002469:Cell Separation / Q000379:methods; D002999:Clone Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D050990:GATA3 Transcription Factor; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D012190:Retroviridae / Q000235:genetics; D050800:STAT6 Transcription Factor; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013269:Stochastic Processes; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection
D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma