International Immunology

International Immunology Advance Access originally published online on September 26, 2008
International Immunology 2008 20(11):1361-1368; doi:10.1093/intimm/dxn106

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review-article

The phenotype of human T_h17 cells and their precursors, the cytokines that mediate their differentiation and the role of T_h17 cells in inflammation

Francesco Annunziato, Lorenzo Cosmi, Francesco Liotta, Enrico Maggi and Sergio Romagnani

Center of Excellence for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies, University of Florence, Florence, Italy

Correspondence to: S. Romagnani, Department of Internal Medicine, University of Florence, Viale Morgagni 85, Firenze 50134, Italy; E-mail: s.romagnani{at}dmi.unifi.it

	Abstract

Top Abstract Introduction Murine Th17 cells Recent discoveries about human... Th17 cell precursors and... Role of human Th17... Conclusions Funding References

 
T helper 17 (T_h17) cells represent a new subset of CD4+ effector T cells which have been described in both mice and humans. However, some differences seem to exist between murine and human T_h17 cells with regard to their features, origin and role in immunopathology. Murine T_h17 cells share their developmental origin with Foxp3+ Treg cells, indeed naive T-cell precursors can be differentiated to regulatory T (Treg) cells by transforming growth factor-β (TGF-β) alone, whereas the contemporaneous presence of TGF-β and IL-6 gives origin to T_h17 cells. Human T_h17 cells which consistently express the CC chemokine receptor 6 and the equivalent of the murine NK1.1, CD161, appear to exclusively originate in response to IL-1β and IL-23 from a small subset of CD161+CD4+ T-cell precursors detectable in the thymus and in umbilical cord blood. These cells constitutively express the T_h17-driving transcription factor retinoic acid-related orphan receptor (ROR)t and the IL-23R and can also give origin to T_h1 cells or T_h2 cells under the appropriate polarizing conditions. By contrast, human CD161-naive T cells only give rise to T_h1 and T_h2 cells, but not T_h17 cells. TGF-β may not exert a direct critical role in human T_h17 cell differentiation, but indirectly favours their development by inhibiting the development of T_h1 cells, which are much more susceptible than T_h17 cells to its suppressive activity on cell proliferation. Moreover, while murine T_h17 are pathogenic in some murine models of autoimmunity where T_h1 cells seem to play a protective role, both T_h17 and T_h1 certainly contribute to the pathogenesis of human autoimmune and other chronic inflammatory disorders.

Keywords: CD161, IL-1β, IL-23, RORt, TGF-β

	Introduction

Top Abstract Introduction Murine Th17 cells Recent discoveries about human... Th17 cell precursors and... Role of human Th17... Conclusions Funding References

 
The adaptive effector CD4+ T helper (T_h)-mediated immune response can be very heterogeneous, because of the existence of distinct subsets characterized by different profiles of cytokine production. Two polarized forms of T_h effectors, named as type 1 (T_h1) and type 2 (T_h2), were initially identified in both mice and humans (1, 2). T_h1 cells produce IFN- and play a critical role in the protection against intracellular microbes. T_h2 cells, which produce IL-4, IL-5, IL-9 and IL-13, but not IFN-, are involved in the protection against gastrointestinal nematodes, as well as in the pathogenesis of allergic disorders. T_h1 cells originate in response to the production of IL-12 and IFNs by dendritic cells and NK cells, whereas T_h2 cells mainly originate from naive T_h cells because of the early presence of IL-4 and in absence of IL-12 during the primary immune response (1, 2). More recently, a novel subset of CD4+ effector T_h cells has been described, which has been named as T_h17, because of its exclusive ability to produce IL-17A in addition to other cytokines, including another member of the IL-17 family, known as IL-17F (3, 4). Although T_h17 cells exist in both mice and humans, some differences seem to exist between the two species. In this review, the main characteristics of human as compared with murine T_h17 cells, as well as the possible role of T_h17 cells in immunopathology, will be discussed.

	Murine Th17 cells

Top Abstract Introduction Murine Th17 cells Recent discoveries about human... Th17 cell precursors and... Role of human Th17... Conclusions Funding References

 
The T_h17 lineage was discovered in some murine models of autoimmunity, such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) (3, 4), which have been historically associated with T_h1 responses. The dogma of the T_h1 role in the pathogenesis of EAE and CIA was challenged by the discovery of a new IL-12 family member, named as IL-23, which shares with IL-12 the p40 subunit, but includes p19 instead of p35.

Indeed, some studies showed that EAE and CIA did not develop in mice deficient in IL-23p19 subunit, whereas both diseases could develop in IL-12p35 subunit-deficient mice (3, 4), thus suggesting that at least in these murine models of autoimmunity IL-23, rather than IL-12, is involved.

A critical role for T_h17 cells in immunopathology and the distinct origin of T_h1 and T_h17 cells under differential IL-12 or IL-23 conditioning was also suggested by findings other than those derived from gene-deficient mice (5). According to the new model, T_h1 and T_h17 cells share their origin from naive CD4+ T-cell precursors and then diverge contingently upon availability during the primary response of IL-12 or IL-23 acting on a common ‘T_h1 precursor’ or ‘pre-T_h1 intermediate’ that co-expresses both IL-12 and IL-23Rs (6–9).

More recently, however, a completely different model of murine T_h17 development has been discovered. Different groups independently demonstrated that transforming growth factor-β (TGF-β) was the critical cytokine for initiation, IL-6 acting as a critical co-factor for T_h17 differentiation (10–12). Notably, TGF-β is also known for its ability to promote the development of T regulatory (Treg) cells that express Foxp3, a transcription factor that acts as the ‘master regulator’ for Treg cells. Nevertheless, the expression of IL-17A or Foxp3 appears to be restricted to separate cell subsets, so that TGF-β-driven T_h17 and Treg development from naive precursors are mutually exclusive. In a more recent study, an IL-6-independent pathway of murine T_h17 differentiation has also been reported, but the nature of the TGF-β co-factor operating in absence of IL-6 remained unclear (13). Moreover, IL-21 has also been found to be involved in murine T_h17 cell differentiation (14, 15).

The transcription factor that acts as a T_h17 master regulator and directs the differentiation program of murine naive T_h cells into T_h17 cells is the retinoic acid-related orphan receptor (ROR)t (16). Up-regulation of RORt is signal transducer and activation of transcription (STAT) 3-dependent since both RORt expression and in vitro T_h17 differentiation are greatly impaired in STAT3-deficient T cells (17). Indeed, STAT3 is activated by IL-6, IL-21 and IL-23 which are also critical for T_h17 development and maintenance (18, 19) and directly binds to the promoter of IL17a/f loci (19). Despite the importance of STAT3 signaling, this stimulus alone appears not to be sufficient to drive T_h17 differentiation. Mice deficient in Rorc gene, which encodes RORt, are unresponsive to IL-23 stimulation, have reduced numbers of T_h17 cells and are resistant to autoimmune diseases (20). However, STAT3 also regulates the expression of RORt, but it is unclear whether this is a direct or indirect effect of STAT3 (20). More recently, high levels of another related nuclear orphan receptor, namely ROR induced by TGF-β and IL-6 and which is also dependent on STAT3, were found in murine T_h17 cells. ROR synergizes with RORt to promote differentiation and function of T_h17 cells (20). Finally, the transcription factor IFN regulatory factor 4 was also recently shown to be essential for murine T_h17 differentiation probably acting upstream of RORt (21). Other factors, such as retinoic acid (22) and aryl hydrocarbon receptors (23), have also been shown to regulate murine T_h17 differentiation. Recent important progress on this point has been achieved with the demonstration that the development of murine T_h17 cells is also regulated by Foxp3 (24–26). Interestingly, Foxp3+ Treg cells were found to be able to produce IL-17 (27).

Murine T_h17 cells produce a large series of cytokines: IL-17A, IL-17F, IL-21, IL-22, IL-26, IL-6 and tumour necrosis factor (TNF)- (28). IL-17A and IL-17F appear to be the key cytokines for the recruitment, activation and migration of neutrophil granulocytes by inducing the production of colony stimulatory factors and CXCL8, which are produced by several cell types, including resident cells (28). IL-21 seems to play an autocrine-amplifying role on T_h17 responses. IL-22 can induce acantosis and dermal inflammation, although in the liver it exhibits a protective role by counteracting the destructive nature of the inflammatory response. The exact role of IL-26 in the T_h17 response has not yet been established (28). Because of their functional properties, T_h17 cells have been suggested to be protective against infections sustained by extracellular Gram-negative bacteria and fungi, in which granulocyte infiltration is usually observed. Accordingly, preferential IL-17 production by T cells has been found during infection by Klebsiella pneumoniae, Bacteroides fragilis, Citrobacter rodentium, Escherichia coli, Borrelia burgdoferi and fungal species, whereas IL-17 plays a modest role (if any) in protecting against intracellular mycobacteria (28).

As mentioned above, T_h17 cells seem to be essential for the induction and propagation of autoimmunity in different animal models. IL-17-deficient mice or mice treated with an IL-17 receptor antagonist are more resistant to the induction of CIA and develop EAE with delayed onset and reduced severity. In this context, the presence, and sometimes the prevalence, of T_h1 cells in the inflammatory tissues of murine autoimmune disorders has been interpreted as a protective, rather than pro-inflammatory, mechanism. This interpretation is based on the following observations: (i) IFN--deficient or IFN- receptor-deficient mice are still susceptible to EAE and CIA (29) and (ii) IFN- inhibits development of T_h17 cells (30).

However, in addition to an impressive series of previous observations clearly demonstrating a pathogenic, rather than protective, role of IFN- in various murine models of autoimmune disorders, very recent findings clearly argue against the exclusive pathogenic role of T_h17, as well as against the protective role of T_h1 cells in all murine models of autoimmunity. Indeed, both IL-12p70-polarized (T_h1) and IL-23-polarized T cells (T_h17) appeared to be able to induce EAE after adoptive transfer (31). Moreover, proteoglycan-induced arthritis, unlike CIA, appears to be completely independent of IL-17 (32). More importantly, it has been clearly established that either T_h1 or T_h17 cells may be pathogenic in murine models of experimental autoimmune uveitis (33). Thus, the T_h17 pathway cannot be called as critical mediator of immune-mediated tissue damage (34), because even T_h1 cells contribute to the inflammatory process.

	Recent discoveries about human Th17 cells

Top Abstract Introduction Murine Th17 cells Recent discoveries about human... Th17 cell precursors and... Role of human Th17... Conclusions Funding References

 
Recent extensive studies have been performed to identify T_h17 cells in humans and to characterize their phenotype and functions. These studies revealed the presence in these cells of RORt, IL-23R and the high expression of the CC chemokine receptor 6 (CCR6), whereas T_h1 cells poorly express CCR6 and highly express the CXC chemokine receptor 3 (CXCR3) (35, 36).

In one of the two studies, T_h17 cells were also found to express the β2 chain of the IL-12R (36). The expression of CCR6 by T_h17 cells has also been described in a murine model of rheumatoid arthritis (RA), where the CXCR3 expression has not been reported (37). Thus, although CCR6 and CXCR3 cannot be considered as selective markers of T_h17 and T_h1 cells, respectively, their detection may be useful for the recognition of the prevalence of each of the two subsets in blood (Fig. 1) or even in inflamed tissues.

View larger version (32K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1. Prevalent expression of CCR6 by Th17 and of CXCR3 by Th1 cells. CD4+ T cells were isolated from the gut of patients affected by CD and expanded in vitro for 1 week with anti-CD3 plus anti-CD28 mAbs in the presence of IL-2. On day 7, cells were stimulated with PMA plus ionomycin for 5 h and assessed by flow cytometry for the surface expression of CCR6 and CXCR3 and for intracellular cytokines production. Among cytokine-producing CCR6+CXCR3– cells, most produced IL-17A alone and few produce IFN- alone; whereas among cytokine-producing CCR6–CXCR3+ cells, virtually all produced IFN- alone. CCR6+CRCX3+ cells were able to produce IL-17A alone, IFN- alone or both IL-17A and IFN-. Data obtained in one of three different donors are reported.

 
Human T_h17 cells exhibited poor proliferative capacity and cytotoxic potential; could induce the production by B lymphocytes of IgG, IgM and IgA, but not IgE and appeared to be less susceptible than T_h1 or T_h2 clones to the suppressive activity of an autologous Foxp3+ Treg clone (36). Moreover, the existence of a remarkable number of either double positive (IFN-+IL-17+) cells in the context of freshly derived blood cells or T-cell clones (named as ‘T_h17/T_h1’ cells) was reported, whereas no clones producing both IL-17 and IL-4 were observed (36). More importantly, both T_h17 and T_h17/T_h1 clones consistently exhibited at both mRNA and protein level not only the expression of RORt but also of T-bet (36), a transcription factor that is the master regulator of T_h1 cells. The incubation of T_h17 clones with IL-12 allowed these cells to produce IFN- in addition to IL-17, and this effect was associated with reduced RORt and increased T-bet expression, suggesting the existence of a flexibility of T_h17 towards T_h1 cells and a possible developmental relationship between the two cell types (36).

More recently, by using a microarray analysis, we provided evidence that human T_h17 cells consistently express on their surface CD161 (38), which is the human homologue of the murine NK1.1 (39). CD161 is expressed on most NK cells and NKT cells and on some T cells and thymocytes. The human CD161+ T_h17 cells were not CD1-restricted NKT cells (40), but CD4+ T cells showing a broad T-cell receptor repertoire and MHC Class II restriction, known as NKT-like T cells (40). Despite the fact that human IL-17-producing cells are not iNKT but NKT-like cells, our findings may appear at variance with those reported in mice showing that a subset of iNKT cells produce IL-17, but curiously while most murine iNKT cells express NK1.1 (NKR-P1C), the IL-17-producing iNKT cells are NK1.1 negative (41, 42). However, by using the microarray assay on murine NKT cells, production of IL-17 by both NK1.1+ and NK1.1– cells upon activation in vitro has also been reported (43). The meaning of CD161 expression by human T_h17 cells is still unclear. One possibility is that this molecule plays an important role in favouring transendothelial migration of T_h17 effectors into tissues, where they are recruited in response to the CCR6-binding chemokine, CCL20. Although the function of CD161 on human T_h17 is unknown, this may represent together with CCR6 an important marker for human T_h17 detection and isolation (Fig. 2).

View larger version (25K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2. Sorting of CCR6+CD161+ circulating T cells allows a strong enrichment of human IL-17A-producing cells. Circulating CD4+ T cells were sorted from one buffy coat for the co-expression of CCR6 and CD161 or of none of them. The resulting cell fractions were assessed upon PMA plus ionomycin stimulation for IL-17A and IFN- production by flow cytometry and then cloned under limiting dilution conditions. A total of 297 and 259 T cell clones were obtained from the CCR6+CD161+ and the CCR6–CD161– cell fractions, respectively. The cytokine profile of T cells clones was assessed by flow cytometry following stimulation with PMA plus ionomycin. The majority of T-cell clones obtained by CCR6+CD161+ cells were composed of IL-17A-producing cells.

 
By looking at the results of the same microarray analysis on human T_h17 clones, among all the genes analyzed, clusterin (CLU) appeared to be down-regulated, whereas Bcl-2 was up-regulated in T_h17 compared with both T_h1 and T_h2 clones (38). Recently, it has been shown that CLU is also a modulator of TGF-β signaling, inasmuch as it is involved in the nuclear translocation of Smad2/3 complex (44), which is critical for the transduction of the TGF-β signaling (45). Proteins of the Bcl-2 family are essential for protecting against apoptosis (46). On the basis of these findings, we evaluated the effect of TGF-β on the proliferation of human T_h17 (i.e. producing IL-17, but neither IFN- nor IL-4), T_h1 (producing IFN-, but neither IL-17 nor IL-4) and T_h2 (producing IL-4, but neither IL-17 nor IFN-) clones, as well as, of circulating CD4+ T cells stimulated by a combination of anti-CD3 and anti-CD28 mAbs. The proliferation of both T_h17 clones and circulating IL-17A-producing T cells was virtually not affected by TGF-β, whereas the proliferation of T_h1 clones and of circulating IFN--producing cells was strongly suppressed (V. Santarlasci et al., unpublished data), suggesting that T_h17 cells are less susceptible to the suppressive activity of TGF-β than T_h1 or T_h2 cells, probably because of their reduced sensitivity to TGF-β signaling and/or increased resistance to apoptotic stimuli.

	Th17 cell precursors and their differentiaton seem to differ in humans compared with mice

Top Abstract Introduction Murine Th17 cells Recent discoveries about human... Th17 cell precursors and... Role of human Th17... Conclusions Funding References

 
The origin of human T_h17 cells, and in particular the role of TGF-β, in their differentiation is still object of an intense debate. Different studies have denied the role of TGF-β in human T_h17 differentiation, rather suggesting the role of IL-1β, IL-23 or IL-6 (47–49). Subsequently, however, three independent studies (50–52) showed that even the differentiation of human T_h17 cells requires the activity of TGF-β, suggesting that previous studies in humans (47–49) have underestimated the role of TGF-β because CD4+ T cells were cultured in media comprising human or bovine serum, which usually contains TGF-β. However, the results of the more recent studies (50–52) are somehow contradictory. Manel et al. (50) found that TGF-β, IL-1β and IL-6, IL-21 or IL-23 were necessary and sufficient to induce IL-17 expression in naive umbilical cord blood (UCB) human CD4+ T cells. TGF-β up-regulated RORt expression but simultaneously inhibited its ability to induce IL-17 expression, an activity which was antagonized by the inflammatory cytokines. Volpe et al. (51) found that TGF-β, IL-23, IL-1β and IL-6 were all essential for human T_h17 differentiation, but they differentially modulated the cytokines produced by T_h17 cells. More importantly, the absence of TGF-β induced a shift from a T_h17 profile to a T_h1-like profile. By contrast, Yang et al. (52) found that TGF-β and IL-21 uniquely promoted the differentiation of human naive CD4+ T cells into T_h17 cells accompanied by expression of RORt.

More recently, we have shown that human IL-17A-producing cells exclusively originate from CD161+CD4+ T-cell precursors present in both UCB and thymus when these cells are activated in presence of a combination of IL-1β plus IL-23 (that could also induce the development of T_h1 cells) (38). No other cytokine or cytokine combinations (including TGF-β, IL-6 and IL-21) was able to induce IL-17A mRNA expression and IL-17A production. Unlike CD161+, CD161–, naive CD4+ T cells from both UCB or thymus could be induced to differentiate into T_h1 or T_h2 cells under appropriate polarizing conditions (IL-1β plus IL-23, or IL-12 alone, for T_h1 cells and IL-4 for T_h2 cells), but they did never differentiate into IL-17A-producing cells (38). Thus, it seems that the small subset of CD161+CD4+ naive T cells present in the thymus and in UCB can give origin to both T_h1 and T_h17 (and also to T_h2) effectors under appropriate microenvironmental conditions, whereas all the other (CD161–) CD4+ naive T cells lack the ability to differentiate into T_h17 cells and can only be induced to differentiate into T_h1 or T_h2 cells. Whether CD161+ and CD161– naive CD4+ T cells represent two distinct lineages or CD161– originate from CD161+ cells remains to be established (Fig. 3).

View larger version (14K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3. Human Th17 cells originate only from CD161+CD4+ T-cell precursors, whereas Th1 and Th2 cells can originate from both CD161+ and CD161– T cells. CD161+CD4+ T cells present in the human thymus or UCB can give rise to Th17, Th1 and Th17/Th1 cells in response to IL-1β and IL-23 and can also differentiate into Th1 cells, in response to IL-12, or to Th2 cells in response to IL-4. CD161–CD4+ T cells can only differentiate into Th1 or Th2, but not Th17, cells. Whether CD161– cells originate from CD161+ cells or they are two distinct lineages is still unknown.

 
The fact that CD161+, but not CD161–, naive CD4+ T cells from both UCB and thymus were found to express constitutively RORt and IL-23R even before their culturing (38) suggests that RORt expression by these cells was not dependent upon exogenously added TGF-β. Moreover, when UCB CD161+ T cells were stimulated in absence or presence of TGF-β alone, or IL-1β plus IL-23, in serum-free cultures, only the addition of IL-1β plus IL-23 significantly enhanced both RORt and T-bet expression, whereas when TGF-β was added together with IL-1β and IL-23 the expression of RORt further increased and T-bet expression strongly decreased. Likewise, the addition of either IL-12 or IL-4 inhibited RORt expression and increased T-bet or GATA-3 expression, respectively (V. Santarlasci et al., unpublished data). TGF-β alone suppressed the ability of cells to produce IFN-, but it did not induce the appearance of IL-17A-producing cells. When TGF-β was added together with IL-1β and IL-23, the proportions of IFN--producing cells were strongly reduced, whereas those of IL-17A-producing cells were enhanced (V. Santaralasci et al., unpublished data). Notably, also in the studies of both Volpe et al. (51) and Yang et al. (52), the induction of IL-17A by TGF-β is associated with a strong decrease of IFN- production.

Our data suggest that TGF-β is not required for RORt expression because CD161+ precursors of IL-17A-producing cells constitutively express RORt. Moreover, TGF-β does not exert a direct critical role on the differentiation of IL-17A-producing cells because the development of IL-17A-producing cells that is induced by IL-1β plus IL-23 could be observed in serum-free cultures even in absence of exogenous TGF-β. The increase of T-bet that was induced by IL-1β plus IL-23 was suppressed when TGF-β was also added and the proportions of IFN--producing cells were strongly reduced, thus resulting in a relative increase in the numbers of T_h17 cells (V. Santarlasci et al., unpublished data). Taken together, these findings support the concept that TGF-β does not have a direct and critical effect on the development of human T_h17 cells, but it can indirectly favour their development by selectively inhibiting both T-bet expression and the development of T_h1 cells (Fig. 4).

View larger version (34K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4. Scheme illustrating the indirect role of TGF-β in favouring human Th17 differentiation. As shown in the upper part, human Th17 cells originate from a small CD161+CD4+ subset of naive T cells present in the thymus and UCB, which constitutively express RORt and IL-23R, in response to the combined activity of IL-1β and IL-23 derived from antigen-presenting cells, whereas under the same experimental conditions CD4+CD161– cells can only develop into Th1 cells. As shown in the lower part, TGF-β does not have a direct effect on human Th17 cell differentiation, but indirectly favours the relative expansion of IL-17A-producing cells by inhibiting the development of Th1 cells.

 

	Role of human Th17 cells in immunopathology

Top Abstract Introduction Murine Th17 cells Recent discoveries about human... Th17 cell precursors and... Role of human Th17... Conclusions Funding References

 
So far, the pathogenic role of T_h17 cells has only been surely established in the so-called hyper-IgE (HIES) or Job's syndrome. Dominant-negative mutations in the DNA-binding domain of STAT3 have been shown to cause this syndrome, because they result in the impaired T_h17 differentiation and the deficiency of T_h17 cells (53). Since T_h17 cells are believed to be critical in the clearance of fungal and extracellular bacteria infections, their deficiency provides the mechanism underlying the susceptibility to the recurrent infections commonly seen in HIES (53–55).

By contrast, the pathogenic role of T_h17 cells in human autoimmune and other chronic inflammatory disorders still needs to be definitively established. Chronically inflamed human tissues in subjects with multiple sclerosis, RA, Crohn's disease (CD) or psoriasis are infiltrated by highly differentiated T_h17 lymphocytes, which produce several inflammatory cytokines, such as IL-17A, IL-22, IL-26, TNF and lymphotoxin-β (56). However, which cytokines produced by human T_h17 cells are involved in the different inflammatory processes, as well as the respective role of T_h1 cells, are still unclear. T_h17 cells appear to enhance osteoclast differentiation, which is required for bone destruction in patients with RA (57). High IL-17 levels have also been found in the sera and colonic biopsies of patients with CD, in whom IL-17F appears to play an important role (58).

Notably, genome-wide association studies have identified the IL-23R gene as being associated with inflammatory bowel disease (59). However, very recently, an IL-23–IFN- axis induced by abnormal intestinal macrophages, more than the IL-23–IL-17 axis, has been found to be important in the pathogenesis of patients with CD (60). High IL-17 levels have also been found in the affected skin of patients with inflammatory skin disorders such as nickel-induced dermatitis, psoriasis and atopic dermatitis (38, 61).

However, some of these findings have been challenged. For example, in a recent study, the frequency of T_h17 cells was significantly decreased in the joints compared with peripheral blood from the same RA patients, whereas T_h1 cells were more abundant in the joints than in peripheral blood (62). Even in psoriasis, which is considered a prototypic T_h17-mediated disease, due to the their ability induce skin acantosis via the production of IL-22 and IL-23 (63), not only T_h17 but also T_h1 cells must be eliminated for final disease resolution (64). With regard to the possible pathogenic role of T_h17 cells in allergic disorders, it has been claimed that these cells may play a critical role in the granulocyte infiltration that is present in the bronchi of some asthmatic patients (65). Obviously, because T_h17 cells have a particular ability to recruit granulocytes, it cannot be excluded that IL-17-recruited cells can enhance bronchial inflammation in severe asthma complicated by bacterial infections and especially in non-allergic asthma. However, it is highly unlikely that T_h17 plays a role in classic IgE-mediated allergic disorders, since the presence of IL-4 is among the most effective inhibitory signals for the differentiation of T_h17 cells in both mice (8) and humans (66).

	Conclusions

Top Abstract Introduction Murine Th17 cells Recent discoveries about human... Th17 cell precursors and... Role of human Th17... Conclusions Funding References

 
The discovery in both mice and humans of a new member of the CD4+ effector T-cell family (T_h17 cells) has provided exciting and novel insights into the immune mechanisms that are responsible for protection and immunopathology. However, some critical differences appear to exist with regard to the mechanisms that are involved in the differentiation of murine and human T_h17 cells, which render it difficult to establish new therapeutic procedures to target these cells or the cytokines that are responsible for their development. In particular, in some murine experimental models of autoimmunity, T_h17 cells share their origin with Treg cells and are pathogenic, whereas T_h1 cells appear to play a protective role. However, other murine models of autoimmunity demonstrate the critical contribution of T_h1 cells to the pathogenesis of the inflammatory process.

Human T_h17 cells appear to have a different origin than in mice. First, human T_h17 cells appear to exclusively originate from a small subset of CD161+ T-cell precursors detectable in UCB and thymus, which constitutively express RORt and IL-23R and develop into T_h17 cells in response to IL-1β and IL-23 in the apparent absence of TGF-β. Notably, the same cytokines also induce the development of T_h1 cells from both the CD161+ and the CD161-naive T-cell subsets, whereas T_h17 cells cannot be generated from the CD161– population. Moreover, even established T_h17 cells can be induced to produce IFN- in addition to IL-17A (T_h17/T_h1 cells), suggesting a common developmental relationship between T_h17 and at least part of T_h1 cells. Whether classic T_h1 cells play a protective role against the pathogenic activity of T_h17 cells or contribute alongside them to the pathogenesis of human autoimmune as well as other chronic inflammatory disorders remains matter of debate.

These findings represent another impressive example of how murine models, although extremely useful, cannot dogmatically be regarded as optimal for the development of novel immunotherapeutic strategies in humans.

	Funding

Top Abstract Introduction Murine Th17 cells Recent discoveries about human... Th17 cell precursors and... Role of human Th17... Conclusions Funding References

 
Ministero dell'Istruzione, dell'Università e della Ricerca, the Italian Ministry of Health, Italian SPATIAL AGENCY (MoMa Project), FP6 European Union project SENS.IT.IV (LSHB-CT 2006-018861), INNOCHEM (FP6-LSHB-CT2005-518167), Legge 5 Regione Campania, 2005, Associazione Italiana Ricerca sul Cancro, Ente Cassa di Risparmio, Florence, Italy.

	Abbreviations

 

CCR6, CC chemokine receptor 6

CD, Crohn's disease

CIA, collagen-induced arthritis

CLU, clusterin

CXCR3, CXC chemokine receptor 3

EAE, experimental autoimmune encephalomyelitis

HIES, hyper-IgE syndrome

RA, rheumatoid arthritis

ROR, retinoic acid-related orphan receptor

STAT, signal transducer and activation of transcription

TGF-β, transforming growth factor-β

Th, T helper

TNF, tumour necrosis factor

Treg cell, regulatory T cell

UCB, umbilical cord blood

	Notes

 
Transmitting editor: H. Kikutani

Received 25 July 2008, accepted 28 August 2008.

	References

Top Abstract Introduction Murine Th17 cells Recent discoveries about human... Th17 cell precursors and... Role of human Th17... Conclusions Funding References

 

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