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A key process in adaptive immunity is the activation of naive CD4+ T cells by antigen presenting cells and their differentiation into effector CD4+ T cells (Milestone 5). Prior to 2005, CD4+ effector T cells were assigned to two helper T cell lineages (TH1 cells and TH2 cells) defined by the cytokines and key transcription factors they expressed (Milestone 11). In 2005, two papers, from Harrington et al. and Park et al., identified and characterized a distinct lineage of CD4+ T cells that produced interleukin 17 (IL-17).

Interferon-γ (IFNγ)-producing TH1 cells are crucial for the clearance of intracellular pathogens, whereas TH2 cells produce IL-4, IL-5 and IL-13 and are involved in the clearance of extracellular pathogens. The search for a third helper T cell lineage was sparked by the work of Langrish et al. They demonstrated that IL-23 could drive the expansion of pathogenic CD4+ T cells that induced autoimmune inflammation in mice. This T cell population produced a unique pattern of pro-inflammatory cytokines, including IL-17, IL-17F, IL-6 and tumour necrosis factor. Following these findings, researchers began to investigate the differentiation requirements for a subset of pathogenic IL-17-producing CD4+ T cells.

Using CD4+ T cells isolated from various strains of mice and differentiated in vitro, Harrington et al. generated IL-17-producing CD4+ T cells, which they called ‘TH17 cells’. These TH17 cells could be generated from CD4+ T cells that were activated with antigen in the presence of IL-23 and the absence of IFNγ and IL-4 signalling. The cytokines IFNγ and IL-4 are key differentiation factors for TH1 cells and TH2 cells, respectively. Thus, the fact that both these factors potently inhibited the development of TH17 cells was further critical evidence of a distinct helper T cell lineage.

Mature TH1 and TH2 cells show phenotypic stability; that is, they do not change their phenotype when restimulated with cytokines from a different helper T cell type. Thus, when Harrington et al. showed that mature TH17 cells were not inhibited by IFNγ or IL-4, they provided further evidence of a distinct lineage. Importantly, the generation of TH17 cells from precursor cells did not require the presence of the TH1 cell transcription factors STAT1 and T-bet, or the TH2 cell transcription factors, STAT4 and STAT6. At this point, however, the identity of a TH17 transcription factor was unknown.

Using cells isolated from different mouse models, Park et al. were also able to generate TH17 cells from CD4+ T cells. Of note, T cell activation requires signalling through costimulatory molecules (Milestone 10), as well as through the T cell receptor (Milestone 8). The generation of TH17 cells required the co-stimulatory molecules CD28 and ICOS. Thus, Park et al. showed that the generation of IL-17-producing TH17 cells required IFNγ- and IL-4-blocking antibodies and the presence of IL-23. Furthermore, the transcription factors STAT4, STAT6 and T-bet were not required for this process. Critically, this study also evaluated the in vivo effects of IL-17 in mice, establishing its role in tissue inflammation.

2006 was another important year for TH17 cell research. Veldhoen et al. further characterized the requirements for TH17 cell differentiation, finding that transforming growth factor-β (TGFβ) and IL-6 have a key role. TGFβ is a crucial factor for the differentiation of regulatory T cells (Treg cells), whereas IL-6 is an acute-phase protein produced during inflammation. Bettelli et al. showed that in the presence of IL-6, the TGFβ-induced differentiation of naive T cells toward the Treg lineage is inhibited and the differentiation is instead skewed toward the TH17 lineage. Interestingly, both studies found that IL-23 was not actually required for TH17 cell differentiation but was instead involved in the survival and expansion of TH17 cells. Subsequently, Ivanov et al. identified the prototypic transcription factor for TH17 cells as the orphan nuclear receptor RORγt.

These studies and others resulted in the identification, characterization and implication of the TH17 cell lineage in a range of immunological contexts and roles in disease.

Further reading

Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

Veldhoen, M. et al. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).