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Roles of interferon-regulatory factors in T-helper-cell differentiation

Nature Reviews Immunology volume 5, pages 125–135 (2005)Cite this article

Key Points

  • Transcription factors of the interferon (IFN)-regulatory factor (IRF) family were originally identified by their capacity to mediate the effects of type I IFNs. Ten IRF-family members have now been defined on the basis of sequence homology and the ability to bind a common DNA motif in various gene promoters.

  • In the past seven years, many IRFs have been found to be involved in T helper (TH)-cell differentiation, a consequence of their capacity to influence the function of accessory cells. This influence leads to alterations in gene products that are important for differentiation into TH1 or TH2 cells, such as interleukin-12 (IL-12), IL-18, IL-23, type I IFNs and nitric oxide.

  • Recent evidence has shown an additional T-cell-intrinsic role for IRF1, -2 and -4 during TH-cell differentiation. This role can be shown even when highly purified naive TH cells are studied in the absence of any accessory cell.

  • IRF1 and IRF2 interact with each other and bind elements in the IL-4 promoter, suppressing its activity.

  • Evidence is accumulating that IRF1 is a multifunctional transcription factor that influences several different cell types and genes to modify the differentiation of TH cells into either TH1 or TH2 cells. Importantly, all of the activities of IRF1 are directed towards a TH1 response, making IRF1 an attractive target for therapeutic intervention in diseases with increased or deficient TH1-cell responses, such as multiple sclerosis or asthma.

  • IRF4 mainly drives TH2-cell development but might also influence TH1-cell development. IRF4 acts intrinsically on TH cells, functions upstream of GATA-binding protein 3 (GATA3) and might interact with signal transducer and activator of transcription 6 (STAT6), B-cell lymphoma 6 (BCL-6) and/or nuclear factor of activated T cells 1 (NFAT1) and/or NFAT2.

Abstract

Members of the interferon-regulatory factor family of transcription factors have long been known to be intracellular mediators of the effects of interferons. In recent years, interferon-regulatory factors have also been shown to have an essential role in the differentiation of T helper cells, both by modulating the functions of antigen-presenting cells and by having direct effects on the T helper cells themselves. Depending on the interferon-regulatory factor involved, the differentiation of T helper cells to either T helper 1 cells or T helper 2 cells can be influenced. In this article, we provide an overview of this relatively new and still underappreciated role of interferon-regulatory factors.

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Figure 1: Structure of interferon-regulatory factors.
Figure 2: Multiple roles of interferon-regulatory factor 1 in differentiation of T helper cells into T helper 1 cells.
Figure 3: Model of differentiation into T helper 2 cells mediated by interferon-regulatory factor 4.

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Acknowledgements

We thank G. S. Duncan (Ontario Cancer Institute, Toronto, Canada), H.-W. Mittrücker (Max–Planck-Institut, Berlin, Germany), T. Matsuyama (Nagasaki University, Nagasaki, Japan) and D. Ferrick (University of California, Davis, United States) for their excellent cooperation during the past few years. We also thank M. E. Saunders for scientific editing. This work was supported by grants from the Deutsche Forschungsgemeinschaft (Germany) and the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Institut für Medizinische Mikrobiologie, Pilgrimstein 2, Marburg, 35037, Germany

    Michael Lohoff

  2. Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario, Canada

    Tak W. Mak

  3. Department of Immunology, 620 University Avenue, University of Toronto, Toronto, M5G 2C1, Ontario, Canada

    Tak W. Mak

  4. Department of Medical Biophysics 620 University Avenue, University of Toronto, Toronto, M5G 2C1, Ontario, Canada

    Tak W. Mak

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  1. Michael Lohoff
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Correspondence to Michael Lohoff or Tak W. Mak.

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DATABASES

Entrez Gene

BCL-6

GATA3

IFN-γ

IL-4

IRF1

IRF2

IRF4

IRF8

STAT1

STAT6

Glossary

VIRUS–IFN AXIS

(Virus–interferon axis). After viral infection, constitutively expressed cytoplasmic IFN-regulatory factor 3 (IRF3) translocates to the nucleus to induce transcription of the IFN-α4 and IFN-β genes. In turn, IFN-α4 and IFN-β induce the expression of IRF7 and thereby the production of other subtypes of IFN-α.

PEST DOMAIN

(Proline-, glutamic-acid-, serine- and threonine-rich domain). A domain that supports the interaction of transcription factors of the ETS family with other transcription factors.

CONCANAVALIN A

(con A). A plant lectin that functions as a T-cell mitogen.

NUCLEAR-LOCALIZATION SIGNAL

A positively charged region of a target protein that binds a cytoplasmic transporter protein. It is responsible for directing the transport of the target protein through nuclear membrane pores and into the nucleus.

PLASMACYTOID DCS

(Plasmacytoid dendritic cells). Immature DCs with a plasmacytoid morphology (that is, similar to plasmablasts), which produce type I interferons in response to viral infection.

ACTIVATION-INDUCED CELL DEATH

(AICD). Apoptotic cell death that is triggered by cellular activation. For example, the death undergone by T helper cells that are activated by CD3-specific antibodies.

ETS SITE

A DNA-binding motif that is recognized by transcription factors of the ETS family. It is a purine-rich sequence that contains the core motif GGAA/T.

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Lohoff, M., Mak, T. Roles of interferon-regulatory factors in T-helper-cell differentiation. Nat Rev Immunol 5, 125–135 (2005). https://doi.org/10.1038/nri1552

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