Diversity and flexibility of Th17 effector functions

IL-17-producing CD4+ T-helper cells (Th17 cells) have been recognised as important drivers of pathogenesis in a multitude of inflammatory diseases, including arthritis. The cytokines and transcription factors that instruct and execute Th17 lineage differentiation have been identified. This has induced hopes that targeting Th17 cells might yield a magic bullet against autoimmune diseases. A new wave of published reports shows that matters are more complicated: Th cells can coexpress IL-17 with a variety of other cytokines, including IFNγ, IL-4, or IL-10, with different functional consequences. Moreover, IL-17 memory is not stable - Th17 cells can be instructed to express other lineage-defining cytokines and to halt IL-17 expression. Finally, Th17 cells may exert tissue-protective effects, even in the context of some inflammatory diseases. Manipulating Th17 cells or IL-17 effects may be more difficult than initially appreciated. Notwithstanding these facts, IL-17 remains a valuable and even more interesting therapeutic target.

Th 17 cells were originally characterised by their coexpres sion of IL-17 (also called IL-17A) together with IL-17F, TNFα, granulocyte-macrophage colony-stimulat ing factor, and lymphotactin, but not Th 1 or Th 2 cytokines [3,4]. Over the past several years it has become clear that Th 17 cells do not represent a homo geneous lineage. IL-17 can be coexpressed with a variety of other cytokines including IL-21, IL-22, IFNγ, IL-10, and IL-4, with consequences for the cells' functionality [1,2,[5][6][7]. Moreover, IL-17 is not exclusively produced by CD4 + cells but also by CD8 + T cells, γδ T cells, natural killer T cells, natural killer cells, and perhaps also neutro phils, mast cells, and others [2]. Not all IL-17 producers therefore are Th 17 cells. One possible current defi nition of Th 17 cells would be CD4 + Th cells that express IL-17A, the IL-23 receptor, and CCR6, and have high levels of expression of the transcription factor RORγt in the absence of signifi cant expression of other lineage-specifi c transcription factors and cytokines. In humans, CD161 expression has been described as a surface marker for Th 17 cells [7].
IL-17A and IL-17F are highly homologous (50% amino acid identity) and share the same receptor. Yet they perform distinct functions. IL-17A seems to be more relevant for the development of autoimmunity and infl am mation than IL-17F, and also plays important roles in the host defence against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defence mechanisms [8].
Th e main physiological function of IL-17 is the recruitment, activation, and migration of neutrophils. Consequently, IL-17 is critically involved in defence against extracellular pathogens, including fungi [9]. Lack of Th 17 diff erentiation or function results in increased susceptibility to extracellular bacterial and fungal infections in humans [10,11].
Th 17 cells are central for the pathogenesis in many murine models of infl ammatory diseases. Th ese cells contri bute to infl ammation through the recruitment of neutrophils and the induction of secretion of proinfl ammatory mediators such as IL-6, IL-8, TNFα, IL-1β, CXCL1, CXCL10, and matrix metalloproteinases from tissue cells [4,9]. In particular, IL-17 is pathogenetically relevant in most murine models of arthritis with the notable exception of proteoglycan-induced arthritis, Abstract IL-17-producing CD4 + T-helper cells (Th17 cells) have been recognised as important drivers of pathogenesis in a multitude of infl ammatory diseases, including arthritis. The cytokines and transcription factors that instruct and execute Th17 lineage diff erentiation have been identifi ed. This has induced hopes that targeting Th17 cells might yield a magic bullet against autoimmune diseases. A new wave of published reports shows that matters are more complicated: Th cells can coexpress IL-17 with a variety of other cytokines, including IFNγ, IL-4, or IL-10, with diff erent functional consequences. Moreover, IL-17 memory is not stable -Th17 cells can be instructed to express other lineage-defi ning cytokines and to halt IL-17 expression. Finally, Th17 cells may exert tissueprotective eff ects, even in the context of some infl ammatory diseases. Manipulating Th17 cells or IL-17 eff ects may be more diffi cult than initially appreciated. Notwithstanding these facts, IL-17 remains a valuable and even more interesting therapeutic target. which is IFNγ dependent [4,12]. Injection of IL-17 into a mouse knee joint induces cartilage degradation, and IL-17 overexpression induces bone erosion and cartilage degrada tion [12]. In man, acting synergistically with IL-1 and TNFα, IL-17 was originally shown to induce massive IL-6 production in synovial fi broblasts [4]. Th e frequency of IL-17-producing cells in the synovium correlates with disease severity in juvenile idiopathic arthritis, rheumatoid arthritis, and psoriatic arthritis [13,14]. In addition, there is a wealth of data demonstrating the presence of IL-17 in infl ammatory lesions in other diseases.
While the prevailing view holds Th 17 cells responsible for pathology in most infl ammatory diseases, recent data also support a tissue-protective function of IL-17 in models of graft versus host disease, colitis, and bronchial hyperreactivity [2]. Whether IL-17-producing Th cells exert pathogenic or protective eff ects depends partly on coexpressed cytokines, tissue-specifi c factors, and the pathogenesis stage. Th cells that coexpress IL-17 and IL-22 together with Th 2 cytokines contribute to the patho genesis of human asthma and a murine model thereof [6], whereas IL-17 alone suppresses bronchial hypersensitivity in the eff ector phase of the disease. In a murine model for multiple sclerosis (experimental autoimmune encephalitis), Th cells that recognise a myelin autoantigen and produce IL-17, IL-22, CXCL10, CCL2, and CCL5 induce disease upon adoptive transfer into recipients. In contrast, IL-17-producing Th cells recognising the same myelin autoantigen, which produce IL-17 together with IL-10, IL-22, and CCL20, are unable to cause disease and even protect recipient mice from the pathogenic eff ect of the aforementioned IL-17 producers [5]. In humans, IL-17-producing RORγt + Foxp3 + T cells that retain their ability to suppress eff ector lymphocytes have been described [9,15]. It is noteworthy in this context that transforming growth factor beta is an important instructive signal for the development of both Th 17 and iTregs. In response to IL-6, the transcription factor IRF-4 suppresses FoxP3 expression while increasing RORγt expression, resulting in the development of Th 17 cells rather than iTregs [16].
Th 17 cells can be converted into other Th subtypes or nonclassical Th 17 cells that coexpress other lineagedefi ning cytokines [1,2,7,9,15,17]. It has become obvious that the expression of cytokines and master transcription factors is fl exible in Th cells [1,2,9,15,17], breaking the dogma of fi xed Th lineages. A thorough appreciation of the fl exibility inherent in Th -cell cytokine production will probably halt the currently popular tendency to label every Th cell that produces a particular combination of cytokines as a distinct T-cell lineage. For example, Th 17 cells can be converted into Th 1/Th 17 cells expressing both IFNγ and IL-17 by combined IFNγ and IL-12 signalling. IFNγ is required to upregulate expression of the IL-12Rβ2 chain, and IL-12 is required for Th 1 polarisation. Th ese Th 1/Th 17 cells stably coexpress RORγt and T-bet [17]. Such fl exibility is pathogenetically relevant. Diabetes induction by adoptive transfer of highly purifi ed Th 17 cells expressing the diabetogenic BDC2.5 T-cell receptor could surprisingly be prevented with antibodies against IFNγ but not with anti-IL-17 antibodies. Isolation and re-analysis of the trans ferred Th 17 cells showed that they had down regu lated RORγt and IL-17 expression and had upregulated T-bet and IFNγ [18]. Jenkins and coworkers demon strated that Th 17 cells elicited in response to Listeria monocytogenes declined faster after the infection than did Th 1 cells [19]. Th eir results suggest that Th 17 cells are less likely to give rise to long-lived memory Th cells, although it is not clear whether the Th 17 cells have lost their IL-17 expression or have died.
In conclusion, given the highly complex mechanisms of diff erentiation, cytokine coexpression, and pathogenic or protective eff ector functions of Th 17 cells, the specifi c modulation of Th 17 eff ector functions is a major therapeutic challenge. Current treatment options for autoimmune diseases include the blockade of IL-1, IL-6, and IL-23 (p40). Since these cytokines are relevant for the induction or maintenance of Th 17 cells, the therapeutic effi cacy may partly be due to reduced IL-17 production. Two human ised antibodies against IL-17A are currently in clinical trial for rheumatoid arthritis, psoriasis, and uveitis, and the fi rst results look promising [20,21]. Th e eff ects of blocking IL-17F alone or together with IL-17A or other IL-17 family members in patients are not yet known. One can safely assume that much will be learned about the relevance of IL-17 family members for human diseases once the data from large clinical trials are publicly available.