The first report on IL-17 producing CD4+
T cells came from a study in which the addition of B. burgdorferi lysate to TcR transgenic T cells induced the production of IL-17 [57
]. However since then, the role of IL-17 and Th17 cells in autoimmune tissue inflammation has been recognized as well. IL-17 is directly involved in cartilage and bone destruction as observed in an experimental model for human rheumatoid arthritis [62
]. Consistent with these observations, IL-17–deficient mice develop reduced collagen-induced arthritis [63
] and treatment with an IL-17R antagonist is sufficient to significantly attenuate adjuvant-induced arthritis in rats [64
]. Similarly, IL-17–deficient animals develop experimental autoimmune encephalomyelitis (EAE) with delayed onset and diminished severity [65
]. In addition, administration of an IL-17-blocking antibody in mice immunized with a myelin antigen prevents chemokine expression in the brain and the subsequent development of EAE [4
Since the expression of IL-17 appeared to be increased in human autoimmune diseases like Multiple Sclerosis [67
], rheumatoid arthritis [69
], and psoriasis [70
] as well as in animal models of autoimmunity, much attention has been focused on defining the role of Th17 cells in the pathogenic process of tissue inflammation [71
]. In the last 3 years the importance of Th17 cells in the pathogenesis of organ-specific autoimmune inflammation has been demonstrated in different animal models. This was paradigm changing, since previously, Th1 cells were considered to be almost exclusively responsible for driving autoimmune tissue damage [72
]. This concept was challenged when it became clear that IFN-γ and IFN-γ-receptor deficient mice as well as mice that lack other molecules involved in the differentiation and stabilization of the Th1 phenotype like IL-12p35, IL-12 receptor-β2, and IL-18 were not protected from EAE, but developed more severe disease [73
]. Furthermore, it was shown that IL-23 and not IL-12 was crucial for mounting an autopathogenic T cell response in the CNS [3
]. Finally, Th17 cells were more potent than Th1 cells in transferring EAE to naïve wild type host animals [4
]. This suggested that Th17 cells might be responsible for the induction of tissue specific autoimmunity. In addition, in chronic inflammatory bowel disease, Th17 cells seem to be essential in inducing the break down of the intestinal epithelial barrier [78
]. Once induced, Th17 cells inhibit the turn-over of colonic epithelial cells and drive immunopathology [79
]. Collectively, these data corroborate the importance of Th17 cells for the induction of autoimmune tissue inflammation.
In the current understanding of the pathogenic process in EAE, antigen specific priming of encephalitogenic T cells as well as their commitment to a certain T helper cell lineage happens in secondary lymphoid tissue outside the central nervous system (CNS). Myelin-specific T cells then traffic to the CNS where they are re-activated [81
]. The efficiency of the activation in situ as well as the acquisition of further effector functions is critical for the maintenance of specific effector populations within the CNS. IL-23 and possibly other cytokines seem to be critical for this process. Indeed, when IL-23 is not available in order to maintain and expand a population of already primed Th17 cells, EAE is markedly attenuated [3
]. Certain adjuvants like zymosan, a constituent of fungal cell walls, are potent inducers of Th17 cells, but do not result in a sufficiently robust IL-23 production by dendritic cells. Using this adjuvant, it has been illustrated that a temporary Th17 response in the secondary lymphoid tissue only resulted in limited tissue inflammation [31
]. Furthermore, it has been shown that both resident microglial cells and infiltrating macrophages were producers of IL-23 [3
]. Given that the lack of p40 in the CNS-APC compartment results in significantly reduced encephalitogenicity of T cells infiltrating the CNS [83
] whereas IL-12p35 deficient mice are extremely susceptible to EAE [75
], it appears that IL-23 expression in the target organ is essential for inducing autoimmune tissue destruction. Collectively, these findings suggest that IL-23p19 is not only required to shape a stable Th17 population in the secondary lymphoid tissue, but also to maintain an encephalitogenic Th17 population in the CNS. Besides IL-23, other cytokines may have a role in stabilizing the phenotype of Th17 cells. For example, in IL-1RI deficient mice, the Th17 response is severely compromised and the animals are resistant to EAE. Thus, IL-1 may contribute to the recruitment and maintenance of Th17 cells [85
]. Although, IL-23 can expand Th17 cells independently of IL-1, it has been shown that IL-23 and TNF may also cooperate to induce IL-1 and drive the expansion of Th17 cells [85
]. Moreover, in animal models of rheumatoid arthritis, IL-17 induces IL-1 in the inflamed synovial tissue [86
]. Hence, IL-17 may be part of a positive feedback loop driven by IL-1.
While IL-23 and possibly IL-1 potentiate Th17 responses, other cytokines like IL-25 (IL-17E) may inhibit Th17 responses. Il25−/−
mice are highly susceptible to EAE due to an enhanced Th17 response. Accordingly, treatment with recombinant IL-25 or IL-25 delivered by a viral vector system is sufficient to suppress EAE in wild type mice [87
]. Although IL-25 is produced by activated Th2 cells, resident cells of the innate immune system like microglial cells are believed to be the major source of IL-25 in CNS autoimmunity. IL-25 may down-regulate the Th17 response in an indirect manner through the induction of IL-13 which inhibitis the production of IL-23, IL-1 and IL-6 in antigen presenting cells [87
]. As previously mentioned, IL-27 is another cytokine with inhibitory effect on the generation of Th17 cells. IL-27 antagonizes the initial lineage commitment of Th17 cells and conversely, IL-27 receptor deficient mice exhibit increased immunopathology in EAE and chronic Toxoplasmosis due to an enhanced Th17 response [40
]. Together, these studies illustrate that the Th17 response is under tight control by a cytokine network whose complexity we are only beginning to understand.
Although Th17 cells are potent inducers of autoimmunity, it is clear that Th1 cells are also involved in the development of autoimmune responses. However, to date, it is not established what are the specific roles and the kinetics of action of these two T helper cell subsets during the development of an autoimmune response. Several points needs to be considered and could explain why Th17 cells are more pathogenic than Th1 cells (see also ): 1) Th17 might migrate in the target organ before Th1 cells, 2) Th17 cells might be necessary to recruit effector T cells to the CNS and 3) Th1 cells might need to cooperate with Th17 cells in order to induce tissue inflammation and destruction. In the natural course of MOG35-55
-induced EAE, the number of Th17 producing CD4+
T cells in the CNS peaks earlier than that of Th1 cells [88
]. Therefore, it is conceivable that Th17 cells are generated and expand faster in response to antigenic challenge and constitute the first wave of effector T cells migrating to the CNS. Consequently, Th17 cells might play a role in the recruitment of further waves of effector T cells, especially Th1 cells (). In support of this hypothesis, IL-17 is an inducer of MCP-1 [35
] that plays a prominent role in the recruitment of mononuclear cells to the CNS [89
]. Furthermore, by inducing IP-10, Th17 cells might drive the migration of Th1 cells that express the IP-10 receptor CXCR3 [90
] into the inflamed tissue. The concept of a specific temporal sequence of various T helper cell subsets infiltrating the target tissue of autoimmune inflammation assumes that the lineage commitment of T helper cells is stable in the target organ. However, whereas in vitro
-differentiation of naive T cells leads to stable lineage commitment, a considerable population of cells secreting both IL-17 and IFN-γ can consistently be observed in vivo
in the target tissue of autoimmune inflammation. This suggests that there may be transitional stages of lineage commitment in vivo
. However, the significance of these cells for the disease process is very unclear at present.
Development of tissue inflammation driven by Th17 cells
To date, it is also uncertain whether Th1 and Th17 cells are equally susceptible to T-reg-mediated suppression in vivo
. The fact that one of the potent immunosuppressive cytokines, TGF-β, which is produced by T-reg, is also required for the differentiation of Th17 cells needs to be taken in consideration. Under inflammatory conditions, notably in the presence of IL-6, T-reg, through their production of TGF-β, might therefore fuel the generation of Th17 cells rather than control it. Moreover, T-reg express the high affinity IL-2 receptor CD25 and may be major consumers of IL-2. Since, IL-2 has been shown to suppress the generation of Th17 cells [10
], the presence of T-reg may also facilitate the differentiation of Th17 by restraining the availability of IL-2.
Collectively, Th17 cells are highly potent inflammatory cells that initiate tissue inflammation and induce the infiltration of other inflammatory cells into the target organ. Hence, at least in relevant mouse models of organ specific autoimmunity, Th17 cells are indispensable for the induction of massive immunopathology. Paradoxically and unlike Th1 cells, Th17 may not be subject to T-reg mediated suppression. However, it appears that in order for Th17 populations to be maintained in the target tissue a complex network of cytokines has to be operative which provides the necessary means to control Th17 cells and may be the basis for the fact that this T cell subset is relatively short-lived and prone to rapid attrition.