Sustained IL-12 signaling is required for Th1 development.
STAT4 is an essential transcription factor for Th1 cell development. IL-12 and IFN-alpha both activate STAT4, but with different kinetics. In this study we compared their capacities to drive differentiation of human naive Th cells toward the Th1 phenotype. The Th1-polarizing activity of IFN-alpha was much weaker than that of IL-12, correlating with a marked difference in the kinetics of STAT4 activation; the response to IL-12 was sustained (>48 h), whereas the response to IFN-alpha was transient (4 h). The continuous presence of IL-12 was required for sustained STAT4 activation. Similarly, optimal Th1 polarization was only achieved upon prolonged exposure to IL-12 and could not be induced by a transient IL-12 pulse. Furthermore, the cytokine IL-2 potentiated sustained IL-12/STAT4 responses through up-regulation of IL-12R expression and synergized with IL-12 in driving Th1 cell development. Transient IFN-alpha responses, on the other hand, were not prolonged by IL-2. IFN-alpha treatment induced down-regulation of IFN-alphabeta receptor subunit 1, rendering cells refractory to IFN-alpha, but did not trans-inhibit the IL-12/STAT4 response. These data indicate that sustained IL-12 signaling is essential for optimal Th1 cell development and that transient activation of STAT4 in response to IFN-alpha may explain the poor Th1-polarizing capacity of this cytokine. Collectively these data show that the duration of cytokine signaling is important for determining the biological response.
Athie-Morales
Veronica
V
Lymphocyte Activation Laboratory and Biochemical Regulatory Mechanisms Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom.
Smits
Hermelijn H
HH
Cantrell
Doreen A
DA
Hilkens
Catharien M U
CM
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D004268:DNA-Binding Proteins / Q000494:pharmacology; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000502:physiology; D016898:Interferon-alpha / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology / Q000502:physiology*; D007376:Interleukin-2 / Q000494:pharmacology; D007399:Interphase / Q000276:immunology; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D007155:Immunologic Factors; D016898:Interferon-alpha; D007376:Interleukin-2; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12