The Journal of Experimental Medicine
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Published online 5 March 2001.
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© The Rockefeller University Press, 0022-1007/2001/3/643/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 5, March 5, 2001 643-650

Brief Definitive Report

An Instructive Component in T Helper Cell Type 2 (Th2) Development Mediated by GATA-3

J. David Farrara, Wenjun Ouyanga, Max Löhningb, Mario Assenmacherd, Andreas Radbruchb,c, Osami Kanagawaa, and Kenneth M. Murphya
a Department of Pathology and Center for Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110
b Deutsches Rheumaforschungszentrum, 10115 Berlin, Germany
c Department of Experimental Rheumatology, Charite, Humboldt University, 10115 Berlin, Germany
d Miltenyi Biotec, 51429 Bergisch Gladbach, Germany

Correspondence to: Kenneth M. Murphy, Department of Pathology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel:314-362-2009 Fax:314-747-4888 E-mail:murphy{at}immunology.wustl.edu.

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.

Key Words: GATA-3, instruction, stochastic, T lymphocytes, cytokine


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