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What does it mean to be just 17?

Naturevolume 441pages166167 (2006) | Download Citation

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For a long time it was thought that there are only two types of T helper cell. But it is becoming clear that there may be other lineages that influence inflammatory responses in certain circumstances.

T cells are a workhorse of the adaptive immune system, with the job of orchestrating defences against microbial invasion. A sub-category of T cells, T helper cells, defends against microbes but also causes trouble by inducing inflammation in immune-mediated diseases. T helper cells become further specialized, or differentiated, and a type known as TH17 has recently stepped into the limelight. These cells produce a messenger molecule called interleukin-17, and are notable both in providing defence against extracellular bacteria and in mediating inflammation.

Research on TH17 cells is at the forefront of immunology, and the latest news comes in three papers1,2,3. Two of them (by Mangan et al.1 and Bettelli et al.2) appear on pages 231 and 235 of this issue, while the third (Langowski et al.3) has just appeared online.

Interferons and interleukins are secreted molecules, also known as cytokines, that both determine T-helper-cell fate and constitute the output of the resulting cells. Conventional thinking was that, in combating infection, T helper cells could take two forms: TH1 cells that produce interferon-γ (IFN-γ), and TH2 cells that produce interleukin-4 (IL-4). The simple TH1–TH2 dichotomy made sense, in that elimination of intracellular pathogens depends on IFN-γ, whereas eradication of parasitic worms requires IL-4 (Fig. 1). But autoimmune diseases do not fit into this picture, into which other subsets of T cells have made their way — first, regulatory T (Treg) cells, which act to keep immune hyperactivity in check, and more recently TH17 cells. Unexpectedly, it is becoming evident that the differentiation of Treg and TH17 cells is related.

Figure 1: T-helper-cell differentiation.
Figure 1

Prompted by different types of interleukin (IL) produced by dendritic cells and other sources, undifferentiated T helper cells can develop into the TH1 or TH2 lineages. In an inflammatory response, TGF-β1 and IL-6 promote the development of another lineage, TH17 cells that produce IL-17. In contrast, interferon-γ (IFN-γ) and IL-4, products of TH1 and TH2 cells, inhibit TH17 differentiation. TGF-β1 boosts expression of the IL-23 receptor, promoting expansion of TH17 cells by IL-23. But TGF-β1 also promotes the development of another lineage — regulatory T (Treg) cells — by inducing the transcription factor Foxp3, an outcome that is inhibited in the presence of IL-6. Development of TH1 and TH2 cells depends on specific STAT proteins and other gene-transcription factors such as T-bet and GATA-3. STAT-3 is probably involved in TH17 differentiation, but other TH17-lineage-specific factors may well emerge.

Interleukin-17, otherwise known as IL-17A, is the founding member of a small family of cytokines, denoted IL-17A–F (ref. 4), that is generally thought to increase inflammation by recruiting other immune cells to peripheral tissues. There is now plenty of evidence that IL-17 has harmful effects in autoimmune and autoinflammatory disorders. TH17 cells have been proposed as a new T-cell lineage that is characterized by the selective secretion of this cytokine. But what governs TH17 production?

Players that lie upstream in the T-helper-cell pathway are dendritic cells, and other so-called antigen-presenting cells, that provide an initial reaction to infection. This response involves the transmission of relevant cytokine signals that prompt the differentiation of specific T-cell populations. Interleukin-23, a cytokine produced by dendritic cells and other antigen-presenting cells, was thought to be required for IL-17 production and subsequent inflammatory disease4. Selective deficiency of IL-23 in mice attenuated immune-mediated disease, resulting in fewer IL-17-producing T cells. More recently, however, a mixture of inflammatory cytokines that includes IL-6 and transforming growth factor (TGF)-β1 was found to be a potent cocktail that results in the production of TH17 cells5.

The studies described in this issue1,2 confirm the role of TGF-β1 and IL-6 in promoting TH17 development, and put to rest the idea that IL-23 is the initiator of TH17 differentiation. Specifically, TGF-β1-deficient mice studied by Mangan et al.1had reduced numbers of TH17 cells, although IL-17 was not completely absent in this setting. Similarly, mice studied by Bettelli et al.2 in which TGF-β1 was overexpressed had increased numbers of TH17 cells and more severe autoimmune disease.

This research1,2 provides strong evidence that TGF-β1 really is necessary for in vivo TH17 differentiation. However, whether other cytokines are required is unresolved. In these studies, TH17 cells were most effectively produced in mixed cell cultures where T cells were stimulated in the presence of antigen-presenting cells. Factors other than IL-6 and TGF-β1 may also be important for this lineage. Moreover, many cells produce TGF-β1 and IL-6, and the main sources of these cytokines for TH17 differentiation remain unclear.

What about IL-23? The receptor for IL-23 is not expressed on precursor T cells, but Mangan et al.1 report that its expression is induced by TGF-β1. So although IL-23 is not an instigator of TH17 differentiation, it may be involved in expanding and maintaining this population of cells.

In all, the new studies1,2 point to the existence of another dichotomy in T-cell differentiation. By itself, TGF-β1 induces the differentiation of Treg cells. The combination of IL-6 in conjunction with TGF-β1 favours IL-17-producing cells, but inhibits the expression of Foxp3, a gene-transcription factor that is essential for Treg differentiation. Thus, TH17 and Treg cells are evidently related, and represent two sides of an inflammatory coin regulated by the same cytokine. The opposing effects of TGF-β1 may seem confusing, but other cytokines have complex dual actions6. It is of interest that there were fewer Treg cells in autoimmune disease associated with TGF-β1 overexpression; perhaps IL-17 antagonizes Foxp3 expression. The counter-regulation of Treg and TH17 will undoubtedly be further analysed.

If IL-23 and IL-17 can be such troublemakers, are they beneficial in host defence? Yes, is the answer. Interleukin-17E has a pivotal role in protection against parasitic worms7,8; and Mangan et al.1 show that IL-23 is necessary for resistance to Citrobacter rodentium, an extracellular bacterial pathogen related to pathogenic Escherichia coli, and the authors argue that IL-23 is important for an effective IL-17 response in vivo. Blocking TGF-β1 also exacerbated disease, again consistent with the importance of this cytokine in in vivo regulation of IL-17. Infection with C. rodentium was associated with some cells that produced both IL-17 and IFN-γ — a notable observation, because the production of these two cytokines was thought to be mutually exclusive.

Clearly, the relationships between TH1, Treg and TH17 cells will need to be further assessed, and much attention has already centred on the gene-transcription factors that drive T-cell differentiation (Fig. 1). Differentiation of TH17 cells seems to be independent of STAT-4 and STAT-6 (transcription factors that regulate TH1 and TH2 cells, respectively). STAT-3 is activated by both IL-23 and IL-6, and binds to the IL-17 and IL-17F gene promoters9. But it remains to be seen whether TH17 cells selectively express lineage-specific transcription factors analogous to two others (T-bet and GATA-3) that are intimately involved in TH1 and TH2 differentiation.

Finally, understanding the regulation of IL-17 takes on additional significance because of a newly identified connection between inflammation and cancer3. The paper concerned, by Langowski et al.3, implicates IL-23 and IL-17 in causing cancer: the authors report that IL-23 and IL-17 are increased in human tumours, and that IL-23 deficiency is associated with fewer tumours in mice that are liable to develop cancer.

It must seem to those outside the business that research developments in immunology merely add complications to our understanding of the immune system. The new papers1,2,3 do indeed add another layer of complexity to T-cell differentiation, and leave many open questions. But they also present exciting data that connect IL-17 regulation with human diseases that range across autoimmunity, infection and cancer, and as such they offer new avenues for the development of treatments.

References

  1. 1

    Mangan, P. R. et al. Nature 441, 231–234 (2006).

  2. 2

    Bettelli, E. et al. Nature 441, 235–238 (2006).

  3. 3

    Langowski, J. L. et al. doi:10.1038/nature04808 (2006).

  4. 4

    Dong, C. Nature Rev. Immunol. 6, 329–333 (2006).

  5. 5

    Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. Immunity 24, 179–189 (2006).

  6. 6

    O'Shea, J. J., Ma, A. & Lipsky, P. Nature Rev. Immunol. 2, 37–45 (2002).

  7. 7

    Fallon, P. G. et al. J. Exp. Med. 203, 1105–1116 (2006).

  8. 8

    Owyang, A. M. et al. J. Exp. Med. 203, 843–849 (2006).

  9. 9

    Chen, Z. et al. Proc. Natl Acad. Sci. USA (in the press).

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  1. the Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, Bethesda, 20892-1820, Maryland, USA

    • Cristina M. Tato
    •  & John J. O'Shea

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