Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells

John T. O'Malley, Sarita Sehra, Vivian T. Thieu, Qing Yu, Hua Chen Chang, Gretta L. Stritesky, Evelyn T. Nguyen, Anubhav N. Mathur, David E. Levy, Mark Kaplan

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

T-cell responses to a cytokine milieu instruct the development of multiple effector phenotypes. While transforming growth factor-β1 (TGF-β1) inhibits the development of T helper type 1 (Th1) and Th2 cells, we demonstrate that like interleukin-6 (IL-6) and IL-4, IL-12 can inhibit the development of TGF-β1-induced Foxp3-expressing adaptive T regulatory (aTreg) cells. Signal transducer and activator of transcription 4 (STAT4) is critical for the response to IL-12, although there is a parallel pathway involving T box expressed in T cells (T-bet), and cells from mice double-deficient in STAT4 and T-bet are refractory to the inhibition of aTreg-cell development by IL-12. While the ability of these cytokines to promote Th differentiation may contribute to this effect, we observe that culture with IL-12, or other instructive cytokines, results in an increase in repressive chromatin modifications at the Foxp3 locus that limit STAT5 binding to Foxp3, without observed effects on IL-2 signalling pathways. In a model of allergic lung inflammation there are increased percentages of Treg cells in the lungs of Stat4-/- mice, compared with wild-type mice, and increases in Treg cells correlate with decreased allergic inflammation. Overall, these results suggest an important role for STAT4 in regulating Treg-cell development.

Original languageEnglish
Pages (from-to)587-595
Number of pages9
JournalImmunology
Volume127
Issue number4
DOIs
StatePublished - Aug 2009

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STAT4 Transcription Factor
Regulatory T-Lymphocytes
Interleukin-12
Transforming Growth Factors
Cytokines
T-Lymphocytes
Th2 Cells
Th1 Cells
Interleukin-4
Chromatin
Interleukin-2
Interleukin-6
Pneumonia
Inflammation
Phenotype
Lung

Keywords

  • Differentiation
  • Interleukin-12
  • Regulatory T cell
  • Signal transducer and activator of transcription
  • Transcription factor

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells. / O'Malley, John T.; Sehra, Sarita; Thieu, Vivian T.; Yu, Qing; Chang, Hua Chen; Stritesky, Gretta L.; Nguyen, Evelyn T.; Mathur, Anubhav N.; Levy, David E.; Kaplan, Mark.

In: Immunology, Vol. 127, No. 4, 08.2009, p. 587-595.

Research output: Contribution to journalArticle

O'Malley, JT, Sehra, S, Thieu, VT, Yu, Q, Chang, HC, Stritesky, GL, Nguyen, ET, Mathur, AN, Levy, DE & Kaplan, M 2009, 'Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells', Immunology, vol. 127, no. 4, pp. 587-595. https://doi.org/10.1111/j.1365-2567.2008.03037.x
O'Malley, John T. ; Sehra, Sarita ; Thieu, Vivian T. ; Yu, Qing ; Chang, Hua Chen ; Stritesky, Gretta L. ; Nguyen, Evelyn T. ; Mathur, Anubhav N. ; Levy, David E. ; Kaplan, Mark. / Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells. In: Immunology. 2009 ; Vol. 127, No. 4. pp. 587-595.
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