A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
Journal: 2005/November - Nature Immunology
ISSN: 1529-2908
Abstract:
Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.
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Nat Immunol 6(11): 1133-1141

A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17

+2 authors
Department of Immunology, University of Washington, Seattle, Washington 98195, USA.
Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Institute for Systems Biology, Seattle, Washington 98103, USA.
Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Correspondence should be addressed to C.D. (gro.nosrednadm@gnodc).
These authors contributed equally to this work.

Abstract

Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-γ negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.

Abstract

CD4 T helper (TH) lymphocytes are essential regulators of immune responses and inflammatory diseases. After being activated by professional antigen-presenting cells (APCs), TH cells differentiate into effector cells specialized in cytokine secretion and function. Effector TH cells have been classified as type 1 (TH1) and type 2 (TH2) based on their cytokine expression profiles and immune regulatory function1. TH1 cells produce interferon-γ (IFN-γ) and mediate cellular immunity, whereas TH2 cells produce interleukin 4 (IL-4), IL-5 and IL-13 and mediate humoral immunity and allergic responses. TH cell differentiation is regulated by the interaction of naive CD4 T cells with innate immune cells that express specific peptide–major histocompatibility complex class II complexes, costimulatory molecules and inflammatory cytokines.

Naive T cell activation normally requires two signals: T cell receptor (TCR) signals, and costimulation through several accessory molecules. The main costimulatory molecule on TH cells is CD28 (ref. 2), which interacts with CD80 (B7-1) and CD86 (B7-2) expressed on mature dendritic cells and other APCs. The inducible costimulator ICOS is another member of the CD28 ‘superfamily’ that also regulates naive CD4 T cell activation and effector differentiation3. In addition to TCR and costimulatory molecules, IL-12 produced by activated APCs is critical in TH1 differentiation4. Additional cytokines in the IL-12 family, IL-23 and IL-27, are also important for TH cell differentiation and function56. IL-23, in particular, is crucial in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis78. Other cytokines also influence the development of effector functions of TH cells; for example, IL-4 produced by activated T cells (and perhaps by other innate cells as well) is crucial in driving TH2 differentiation9.

TH differentiation and effector cytokine expression are mediated by several key transcription factors. IL-12 regulates TH1 differentiation through activation of the transcription factor STAT4 (refs. 45). The transcription factor T-bet is a ‘master regulator’ of TH1 differentiation through the potentiation of IFN-γ production and suppression of TH2-associated cytokine expression4. IL-4, in contrast, drives TH2 differentiation through the actions of STAT6 (ref. 9) and GATA-3, which is a ‘master regulator’ of TH2 differentiation through potentiation of IL-4 and suppression of IFN-γ10. In addition, c-Maf has been identified as a TH2-specific transcription factor that binds to the Il4 proximal promoter11. Studies of Maf-knockout mice and mice with overexpression of a Maf transgene, furthermore, have indicated that c-Maf selectively regulates Il4 expression1112.

IL-17 (also called IL-17A) has been associated with many inflammatory diseases such as rheumatoid arthritis, asthma, lupus and allograft rejection1315. The IL-17 receptor (IL-17R) is distributed ubiquitously in various tissues14, and its engagement activates both transcription factor NF-κB and kinase Jnk pathways16. Many in vitro studies have indicated a proinflammatory function for IL-17 (ref. 15). In particular, IL-17 has been linked to tissue neutrophil recruitment through the induction of granulocyte colony-stimulating factor and IL-8 (ref. 15), and IL-17R-deficient mice have impaired host defense against microbacterial infection because of a substantial reduction in granulocyte colony-stimulating factor and macrophage inflammatory protein 2 in the lung17. IL-17 is also important in contact, delayed-type and airway hypersensitivities, as shown in a study using IL-17-deficient mice18. In related reports, IL-17-deficient mice19, as well as wild-type mice that received an IL-17R antagonist20, have shown resistance to an arthritis-like disease.

IL-17 expression is generally thought to be restricted to T cells. In humans, IL-17 is expressed by activated CD4 T cells and by TH1 and TH0 cells but not by TH2 cells21, whereas in mice, IL-17 expression is strongly induced by IL-23 in memory T cells22. Notably, IL-23 (but not IL-12) deficiency is associated with resistance to EAE and collagen-induced arthritis78, a phenotype that correlates with a defect in IL-17 expression823. IL-23 also selectively expands IL-17-expressing T cell populations, which may also coexpress another IL-17 family cytokine, IL-17F, as well as tumor necrosis factor (TNF) and IL-6 (ref. 23). These data suggest that a unique cytokine requirement is needed for generating T cells that express IL-17.

Here we have analyzed the regulation and function of IL-17 in vitro and in vivo. We found that IL-17 was expressed by a distinct lineage of TH effector cells; generation of these cells required CD28 and ICOS costimulation and was independent of the cytokine and transcription programs normally associated with TH1 and TH2 differentiation. In vivo, IL-17 potently regulated chemokine expression by tissue cells, and IL-17 overexpression in the lung caused airway inflammation. In contrast, IL-17-specific inhibition attenuated immune infiltration in the brain in an EAE model. We conclude from these data that IL-17 is expressed by a previously unknown subset of TH cells and is crucial in regulating tissue inflammatory reactions.

Footnotes

COMPETING INTERESTS STATEMENT

The authors declare that they have no competing financial interests.

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Footnotes

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