Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 2015 Mar;144(3):343–351. doi: 10.1111/imm.12399

Human T helper type 1 dichotomy: origin, phenotype and biological activities

Francesco Annunziato 1,2, Lorenzo Cosmi 1,2, Francesco Liotta 1,2, Enrico Maggi 1,2, Sergio Romagnani 1,✉
PMCID: PMC4557671  PMID: 25284714

Abstract

The great variety of pathogens present in the environment has obliged the immune system to evolve different mechanisms for tailored and maximally protective responses. Initially, two major types of CD4+ T helper (Th) effector cells were identified, and named as type 1 (Th1) and type 2 (Th2) cells because of the different cytokines they produce. More recently, a third type of CD4+ Th effectors has been identified and named as Th17 cells. Th17 cells, however, have been found to exhibit high plasticity because they rapidly shift into the Th1 phenotype in the inflammatory sites. Therefore, in these sites there is usually a dichotomous mixture of classic and non-classic (Th17-derived) Th1 cells. In humans, non-classic Th1 cells express CD161, as well as the retinoic acid orphan receptor C, interleukin-17 receptor E (IL-17RE), IL-1RI, CCR6, and IL-4-induced gene 1 and Tob-1, which are all virtually absent from classic Th1 cells. The possibility to distinguish between these two cell subsets may allow the opportunity to better establish their respective pathogenic role in different chronic inflammatory disorders. In this review, we discuss the different origin, the distinctive phenotypic features and the major biological activities of classic and non-classic Th1 cells.

Keywords: cell differentiation, T cells, T helper type 1/type 2/type17 cells

Introduction

The great variety of pathogens and other antigens existing in the environment has determined the need for the immune system to evolve different mechanisms of protection. In the context of adaptive immunity, the effector functions are mediated by CD8+ cytotoxic T cells and by CD4+ T helper (Th) cells. CD4+ Th cells have been distinguished into two major types, designated type 1 (Th1) and type 2 (Th2) on the basis of different cytokines they produce.1–4 Th1 cells produce interferon-γ (IFN-γ) as their signature cytokine, whereas Th2 cells produce interleukin-4 (IL-4), IL-5 and IL-13. A third type of effector CD4+ T cell was then discovered in both mice and humans and named as Th17 because of its unique ability to produce IL-17.5–7 However, the study of Th17 cells has allowed us to demonstrate their high flexibility because they rapidly shift to the Th1 cell phenotype.7,8 Hence, a dichotomy appears to exist and the two types of Th1 cells have been defined as classic (the initially discovered) and non-classic (the Th17-derived) Th1 cells.9,10 In this review, we will discuss the differences in phenotype, origin and biological activities of classic and non-classic Th1 cells in view of their possible different roles in protection and immunopathology.

Classic Th1 cells

Classic Th1 cells originate from naive CD4+ Th cells, which exit the thymus and enter secondary lymphoid organs with the majority populating lymph nodes. The naive CD4+ Th cell differentiation into a Th1 cell occurs when their T-cell receptor (TCR) encounters its cognate antigen bound to the MHC class II molecules on the antigen-presenting cell. Upon TCR engagement a number of factors influence the differentiation process toward the Th1 (or Th2) lineage, including the type of antigen-presenting cell, the concentration of antigen (duration and strength of signal), the ligation of selected co-stimulatory molecules, and the local cytokine environment. The environmental cytokine mainly responsible for human Th1 cell differentiation is IL-12,11,12 which is produced by dendritic cells (DCs) in response to the interaction of their innate sensors, known as pattern recognition receptors, with bacterial or viral conserved structures.13 The activity of IL-12 can be potentiated by another cytokine, IL-18, which is produced by several immune and non-immune cells.14 Interferon-γ also contributes to the Th1 cell differentiation, and at least in humans, IFN-α is also involved in this process.15 Interferon-γ is produced by natural killer cells and IFN-α by plasmocytoid DCs. The role of IL-12 and IFNs produced by DCs and natural killer cells in Th1 cell differentiation allowed us to suggest more than 20 years ago that the type of adaptive cell-mediated immunity could be heavily influenced by the nature of the innate immunity.16 More recently, two other cytokines, IL-23 and IL-27, have been found to be express a Th1-polarizing activity.17 In addition to the environmental cytokines produced by cells of the innate immune system, the interaction between co-stimulatory molecules can also contribute to Th1 cell differentiation. For example, the interaction between CD40 expressed by DCs or macrophages and the CD40 ligand (CD154) is able to amplify the production of IL-12.18 Moreover, a similar effect was found following the interaction between the Notch ligand Delta on murine DCs and the Notch receptor expressed by T cells.19 Similarly, expression of Delta-4 by human mature DCs and its interaction with Notch on T cells allowed Th1 polarization.20 Activation of the signal transducer and activator of transcription 1 (STAT1) by IFN-γ and of STAT4 by the interaction of IL-12 with its receptor (IL-12R) is critical for the induction of T-box expressed in T cells (T-bet), which is considered to be the hallmark transcription factor for Th1 cells, inasmuch as it is able to bind the IFN-γ promoter and to induce the production of IFN-γ.21 In addition to the production of IFN-γ and the expression of T-bet, Th1 cells are also characterized by the expression of selected chemokine receptors, which allow their recruitment in the inflammatory sites. The main chemokine receptors of Th1 cells are CXCR3A and CCR5. Hence, CXCL9, CXCL10 and CXCL11 (CXCR3 ligands) and CCL3, CCL4 and CCL5 (CCR5 ligands) mainly contribute to the Th1 cell recruitment.22,23 Moreover, through the production of IL-2 and IFN-γ, Th1 cells can also potentiate the activity of CD8+ cytotoxic T cells (Tc1), of NK cells, and of the more recently discovered group 1 innate lymphoid cells,24 thus amplifying the response of the CD8+ T-cell branch of adaptive immunity, as well as the activities of the native, effector immunity. The mechanisms involved in the development of Th1 cells and their major biological activities are depicted in Fig.1. Th1 cells were found to have not only a protective role, but they may also be responsible for many chronic inflammatory disorders, especially organ-specific autoimmune disorders, such as Hashimoto’s thyroiditis,25 multiple sclerosis,26 insulin-dependent diabetes mellitus,27 but also for other chronic inflammatory disorders, such as rheumatoid arthritis,28 Crohn’s disease,29 sarcoidosis,30 acute allograft rejection31 and atherosclerosis,32,33 whereas Th2 cells were mainly found to be responsible for atopic allergic disorders.34 For many years, this has been known as the Th1/Th2 paradigm.35

Figure 1.

Figure 1

Open in a new tab

Mechanisms of differentiation and major biological activities of classic T helper type 1 (Th1) cells. Pattern recognition receptors (PRRs) present on myeloid dendritic cells (mDCs) recognize the pathogen and are induced to its processing and to their migration to the regional lymph node, where they present pathogen peptides associated with class II MHC to naive CD4+ T cells. In the presence of interleukin-12 (IL-12) produced by mDCs, interferon-γ (IFN-γ) produced by natural killer (NK) cells/innate lymphoid cells (ILC1), and IFN-α produced by plasmacytoid DCs (pDC), naive CD4+ T cells develop into Th1 cells. IL-18 and IL-27 also contribute to Th1 differentiation. The production of IL-12 is also favoured by the interaction between Notch expressed by the naive T cell and its ligand Delta expressed on DCs. Polarized Th1 cells are able to produce IFN-γ and leukotriene-α (LT-α) as their signature cytokines and also IL-2 and tumour necrosis factor-α (TNF-α). After their migration into the pathogen-affected site, IFN-γ produced by Th1 cells activates macrophages (Mo) to produce metalloproteinases (MMP), nitric oxide (NO) and pro-inflammatory cytokines, which favour the killing of phagocytosed microbes. IFN-γ and IL-2 also contribute to the microbe removal by involvement in the response of ILC1 and NK cells, as well as Tc1 cells, the latter being capable of direct killing of the infected cells.

Beyond the Th1/Th2 paradigm: the discovery of Th17 cells

Murine Th17 cells

The Th1/Th2 paradigm was maintained until some years ago when a third subset of CD4+ effector Th cells, named Th17 cells, was identified. The breakthrough leading to the discovery of the Th17 lineage came from murine models of autoimmunity such as experimental autoimmune encephalomyelitis, collagen-induced arthritis and inflammatory bowel disorders. The link with IL-12 in these diseases was called into question by the discovery that a new IL-12 family member, IL-23, shares with IL-12 the p40 subunit, the heterodimer of IL-12 being composed of p40 and p35, and that of IL-23 being composed of p40 and p19.36 Interleukin-23 shares with IL-12 also a chain of its receptor, the IL-12 receptor being composed of IL-12Rβ1 and IL-12Rβ2 chains, and that of IL-23 being composed of IL-12Rβ1 and IL-23R chains. After this discovery, it was found that experimental autoimmune encephalomyelitis and collagen-induced arthritis did not develop in mice deficient in IL-23p19 subunit or IL-23R chain, whereas they could develop in those deficient in IL-12p35 subunit or IL-12Rβ2 chain, suggesting that at least in these models IL-23, but not IL-12, is critically linked to autoimmunity.37,38 Subsequently, however, a completely different pathway of murine Th17 origin was described. Although IL-23 appeared to be required for Th17-induced immunopathology, different groups independently demonstrated that transforming growth factor-β (TGF-β) was required for initiation and that IL-6 was a critical co-factor for Th17 differentiation.5,39,40 Of note, the Th17-polarizing cytokine TGF-β was already known for its ability to promote the development of Foxp3+ Treg cells, but only in the absence of IL-6.41 Murine Th17 cells express a master transcription factor different from Th1 and Th2 cells, an orphan receptor known as retinoic acid-related orphan receptor (ROR)-γt.42 A second orphan receptor, named as ROR-α, has been found to contribute to the development of murine Th17 cells.43 The STAT3 transcription factor is also essential for murine Th17 development.44 The distinctive cytokine of murine Th17 cells, IL-17A, is involved in the recruitment, activation and migration of neutrophil granulocytes by inducing the production of colony-stimulatory factors and CXCL8 by both macrophages and tissue-resident cells.45 The other cytokines produced by murine Th17 cells, such as IL-17F, IL-21 and IL-22, can also contribute to the activation of mononuclear and/or resident cells and therefore may induce and/or maintain a chronic inflammatory process.46 However, because of their unique ability to recruit neutrophils, the main protective function of Th17 cells appears to be the clearance of extracellular pathogens, including fungi.46 Nevertheless, the major emphasis on the pathophysiology of murine Th17 cells was placed on their determinant or even exclusive pathogenic role in models of autoimmunity.47 This concept was immediately extrapolated to human disorders, which are considered as equivalent to the aforementioned murine models, such as multiple sclerosis, rheumatoid arthritis and Crohn’s disease, but also to psoriasis and contact dermatitis. Therefore, Th17 cells were thought to be the pathogenic cells in almost all chronic inflammatory disorders, and the role of Th1 cells, which had been shown to be important in hundreds of previous studies, was underscored or even seen as protective against the Th17-mediated inflammation.48

Human Th17 cells

The clear evidence on the existence, phenotype and functional activity of human Th17 cells was given by different groups in 2007.6,7,49,50 Human Th17 cells were found to produce the same cytokines as murine Th17 cells, express the transcription factor RORC (equivalent of the murine RORγt), the IL-23R and the chemokine receptors CCR4 and CCR6.6,7 However, human Th17 cells were found to be different from murine Th17 cells, because apparently they did not require the addition in culture of TGF-β for their differentiation. Following TCR triggering, the presence in culture of IL-1β (or IL-6) and IL-23 was found to be sufficient, even in the absence of TGF-β.51,52 The need for TGF-β for Th17 cell differentiation has then been questioned even in mice.53,54 In our studies, it was found that, unlike murine Th17 cells, human memory Th17 cells expressed CD161 and appeared to originate from a fraction of naive CD161+ Th cell precursors, detectable in both umbilical cord blood and newborn thymus, when their TCR was activated in the combined presence of IL-1β and IL-23 and even in the absence of TGF-β.52 The mechanisms of development of human Th17 cells and the major biological activities of these cells are depicted in Fig.2.

Figure 2.

Figure 2

Open in a new tab

Mechanisms of differentiation and major biological activities of T helper type 17 (Th17) cells. Pattern recognition receptor-expressing dendritic cells (DCs) may also present the pathogen peptides associated with class II MHC in the regional lymph node or in the lymphoid mucosal tissue to a different subset of naive CD4+ Th cells which express CD161. In the presence of interleukin-1β (IL-1β) and IL-23, CD4+ CD161 naive T cells develop into Th17 cells, which produce IL-17A, IL-17F and IL-22. The IL-17A and IL-17F activate epithelial cells, endothelial cells, fibroblasts and macrophages. All these cells also produce CXCL8, a chemokine able to recruit neutrophils. Neutrophils and activated macrophages, which produce matrix metalloproteinases (MMP), nitric oxide (NO), pro-inflammatory cytokines and anti-microbial peptides, create a strong inflammatory environment, so providing protection against extracellular bacteria and fungi. IL-22 contributes to the protection by providing an important function for the epithelium homeostasis.

One of the peculiar features of Th17 cells in comparison with Th1 and Th2 cells is their rarity in the inflammatory sites. There are various reasons for the rarity of human Th17 cells in chronic inflammatory disorders. The first is the existence of different self-regulatory mechanisms that limit their expansion. In the last few years we have identified at least two different limiting mechanisms: (i) the poor ability to produce IL-2 in response to TCR signalling, and (ii) the reduced capacity to enter into the cell cycle. The defect in IL-2 production was the result of the abnormally high expression in Th17 cells of IL-4-induced gene 1 (IL4I1),55 which encodes a secreted l-amino-acid oxidase56 that inhibits human T-lymphocyte proliferation in vitro by inducing a temporary decrease in CD3ζ chain expression via the enzymatic production of H2O2.57 The high IL4I1 mRNA expression in Th17 cells was regulated by Rorc, in as much as its product directly bound to the IL4I1 promoter.55 In a subsequent study, we have shown that IL4I1 also maintains in human Th17 cells high levels of Tob1,58 a member of the Tob/BTG anti-proliferative protein family, which prevents the cell cycle progression mediated by TCR stimulation. Even the high Tob1 expression in human Th17 cells was related to IL4I1, inasmuch as IL4I1 silencing induced a substantial decrease of Tob1.58

The flexibility of Th17 cells and their shift to non-classic Th1 cells

The other important reason for explaining the rarity of Th17 cells in the inflammatory sites is their high plasticity, which allows these cells to produce IFN-γ and then rapidly shift to the Th1 phenotype. The first demonstration of the Th17 cell shifting towards the Th1 phenotype was provided in our initial study on these cells.7 As expected, the majority of T cells derived from the inflamed mucosa of patients with Crohn’s disease were characterized by the production of IFN-γ, but there were also a few T cells producing IL-17, but not IFN-γ (Th17 cells), and other cells producing both IL-17A and IFN-γ, that we named Th17/Th1 cells.7 To investigate the origin of these Th17/Th1 cells, we cultured Th17 cell clones in vitro in the presence of IL-12. After 1 week of culture, a proportion of Th17 cells started to produce IFN-γ and after 2 weeks all of them shifted towards the Th1 phenotype.7 The shifting of human Th17 cells was then clearly demonstrated to occur even in the synovial fluid of children affected by juvenile idiopathic arthritis and found to be dependent on the activity of IL-12 present in the synovial fluid.59 In a subsequent study, we have shown that human Th17 cells can also be shifted to the Th1 phenotype in the presence of tumour necrosis factor-α (TNF-α), inasmuch as treatment of juvenile idiopathic arthritis patients with Etanercept (a TNF-α antagonist) partially inhibits this shift.60 The transient nature of the Th17 phenotype was then considered as an established fact even in mice.8 In addition to IL-12 and TNF-α, other pathways have been identified that induce IFN-γ production by Th17 cells. Interferon-γ itself can render Th17 cells sensitive to IL-12.61 Moreover, repeated stimulation of Th17 cells in the presence of IL-23 can directly up-regulate IFN-γ independently of T-bet.62 Recently, Duhen and Campbell63 identified IL-1β as a key cytokine that renders Th17 cells sensitive to IL-12, and both cytokines together potently induced the differentiation of cells that produce IL-17, IFN-γ and granulocyte–macrophage colony-stimulating factor (GM-CSF), and the contemporary production of the three cytokines has been associated with pathogenicity in autoimmune diseases. Therefore, Th17 cell plasticity may be governed in vivo by multiple pathways depending on the cytokine micro-environment (Fig.3) and interfering with this mechanism might prove more challenging than previously anticipated (see below). We have defined Th17-derived Th1 cells as non-classic so as to distinguish them from classic Th1 cells,9 and we have also tried to identify the main differences between the two types of cells.10

Figure 3.

Figure 3

Open in a new tab

Mechanisms inducing the shifting of T helper type 17 (Th17) cells to non-classic Th1 cells. In the inflammatory environment, Th17 cells are induced by interleukin-12 (IL-12) and tumour necrosis factor-α (TNF-α), particularly in the presence of IL-1β, as well by the repeated exposure to IL-23, to shift from the production of IL-17A, IL-17F and IL-22 to the production of interferon-γ (IFN-γ) and granulocyte–macrophage colony-stimulating factor (GM-CSF) in addition to IL-17A and IL-22 (Th17/Th1 cells), and then to the production of GM-CSF and IFN-γ alone (non-classic Th1 cells).

Phenotypic discrimination between classic and Th17-derived (non-classic) Th1 cells

The main features of classic and non-classic Th1 cells, which allow to the existence of a true dichotomy within the Th1 cell population to be revealed, are depicted in Table1. Classic Th1 cells express T-bet and CXCR3, whereas non-classic Th1 cells express both T-bet and RORC2, IL-4I1, Tob-1, CCR6, IL-1RI, IL-23R and IL-17RE.10 More recently, we also looked at possible differences in the epigenetic regulation between non-classic and classic Th1 cells. As expected, non-classic Th1 cells exhibited complete demethylation of the analysed regions of interest of RORC2 gene promoter, as happens in Th17 cells, as well as partial methylation of the analysed regions of interest in IL-17A gene promoter, whereas classic Th1 cells did not (A. Mazzoni, V. Santarlasci, L. Maggi, M. Capone, M. C. Rossi, V. Querci, R. De Palam, H.-D. Chang, A. Thiel, F. Liotta, L. Cosmi, E. Maggi, A. Radbruch, S. Romagnani, J. Dong, F. Annunziato, unpublished data).

Table 1.

Distinctive features of classic and ‘non-classic’ human T helper type 1 cells

Feature Classic Th1 cells Non-classic Th1 cells
Cell source CD61− naive Th cell Activated Th17 cell
Site of differentiation Lymph nodes Inflammatory sites
Polarizing cytokines IL-12, IL-18, IFNs IL-12, TNF
Transcription factors T-bet T-bet, RORC
Surface receptors
 Chemokine receptors CXCR3, CCR5 CXCR3, CCR6
 Cytokine receptors IL-12, IL-18 IL-1β, IL-23, IL-12, IL-17RE
 Other CD161
Regulatory genes for proliferation (mRNA expression) IL-4I1, Tob-1
Methylation status
 RORC2 Hypermethylated Hypomethylated
 IL-17 Hypermethylated Hypomethylated
 T-bet Demethylated Demethylated
 IFN-γ Demethylated Demethylated
Open in a new tab

Abbreviations:IFN-γ, interferon-γ; IL-12, interleukin-12; RORC, retinoic acid-related orphan receptor C; Th1, T helper type 1; TNF, tumour necrosis factor.

Possible different functional role of the two Th1 subsets

The protective role of classic Th1 cells is well established. Th1 cells, mainly because of their ability to activate mononuclear phagocytes via the production of IFN-γ, play an important role in defence against intracellular bacteria, such as Mycobacterium tuberculosis, Leishmania major, Toxoplasma gondii and many others.64 Intracellular bacteria or protozoans are endowed with the capacity to survive and replicate inside mononuclear phagocytes and, sometimes, within certain other host cells. Mononuclear phagocytes are potent effector cells that are able to engulf and kill many bacterial invaders. Therefore, intracellular bacteria must exploit potent evasion mechanisms that allow their survival in this hostile environment. During intracellular persistence, microbial proteins are processed and presented, so initiating T-cell activation. By secreting IFN-γ and TNF-α, Th1 cells activate mononuclear phagocytes, converting them from a habitat to a potent effector cell. Hence, infections sustained by intracellular bacteria are mainly associated with a systemic response of classic Th1 cells and a subsequent activation of mononuclear phagocytes.64 Classic Th1 cells are even important for the protection against certain viruses, because in addition to the ability to produce IFN-γ and TNF-α, which contribute to the activation of CD8+ cytotoxic T cells, Th1 cells themselves exhibit cytolytic activity.11,16 The first suggestion for a possible antiviral activity of Th1 cells, at least against RNA viruses, was provided by the observation that polyinosinic acid: polycytidylic acid promotes Th1-specific immune responses by stimulating macrophage production of IFN-α and IL-12.65 It was subsequently demonstrated, although long questioned, that a shifting from Th1 to Th2 phenotype may be associated with the progression of HIV infection to full blown AIDS.66

The protective role of non-classic Th1 cells is at present less clear, because these cells usually appear in the inflammatory sites as a consequence of the shifting of Th17 cells.

Pathogenic role of the non-classic Th1 subset in human chronic inflammatory disorders

As noted above, Th17 cells are not an end stage of effector T-cell differentiation, because a substantial proportion of human Th17 cells acquire or up-regulate Th1-associated markers, including expression of IFN-γ, CXCR3 and T-bet, still maintaining Th17-associated markers such as CD161, IL1-R1, IL-23R, IL-17RE, RORC2, IL4I1, Tob1 and CCR6. The notion that Th17 cells are precursors that differentiate into non-classic Th1 effector progeny in a progressive, linear fashion in inflamed tissues is suggested by the ratio of these subsets found in autoimmune target organs. Indeed, Th17-derived Th1 cells, but not Th17, as well as classic Th1 cells, constitute the majority of tissue-infiltrating CD4+ T cells in the joints of patients with rheumatoid arthritis,59,67 the affected gut of patients with Crohn’s disease7,68,69 and the cerebrospinal fluid of patients with multiple sclerosis.70 Recent studies in mice indicate that IL-17A expression is not sufficient to define Th17 cells with pathogenic activity. Pathogenic murine Th17 cells express a unique transcriptional signature compared with non-pathogenic Th17 cells, which includes elevated expression of the IL-23R. Accordingly, IL-23R-deficient Th17 cells cannot induce autoimmune pathology.71 Using IL-23R expression levels as a surrogate to define the pro-inflammatory potential of human effector T-cell subsets, it has been shown that IL-23R expression does not track with that of canonical Th17 cytokines (IL-17A) but rather is increased in CCR6+ CXCR3+ Th17 subsets able to produce IFN-γ.71 Previous studies in mice suggested that IL-23 causes inflammation by promoting GM-CSF and IFN-γ expression in Th17 cells, and that GM-CSF-deficient Th17 cells fail to induce adoptively transferred experimental autoimmune encephalomyelitis.72 More recently, Piper et al.73 showed an enrichment of GM-CSF-producing Th cells in the joints of patients with juvenile idiopathic arthritis and, notably, the frequency of these cells was directly correlated with levels of GM-CSF protein in the joint and of serum markers of disease activity. More importantly, the same authors also demonstrated that GM-CSF-expressing T cells in human autoimmune disease have a phenotype associated with ex-Th17 cells (non-classic Th1 cells), expressing RORC2, CD161 and IFN-γ, but not IL-17A, and that the cytokine driving the polarization of Th17 cells towards the non-classic Th1 phenotype, IL-12, is also involved in the induction of GM-CSF production.73 Additional evidence on the pathogenic role of Th17-derived Th1 cells (non-classic Th1) come from the recent study by Ramesh et al.74 In this study the authors showed that pro-inflammatory human Th17 cells are restricted to a subset of CCR6+ CXCR3hi CCR4lo CCR10− CD161+ cells that express c-Kit transiently and P-glycoprotein (P-gp)/multi-drug resistance type 1 (MDR1) stably. MDR1+ Th17 cells produce both Th17 (IL-17A, IL-17F, GM-CSF and IL-22) and Th1 (IFN-γ) cytokines upon TCR stimulation. These cells also display a transcriptional signature similar to that of pathogenic murine Th17 cells and show heightened functional responses to IL-23 stimulation. In vivo, MDR1+ Th17 cells are enriched and activated in the gut of Crohn’s disease patients.74

Possible implications of the Th1 dichotomy for the choice of novel immunotherapeutic strategies

As mentioned above, the ability of Th17 cells to respond to pro-inflammatory cytokines, i.e. IL-23, IL-12, TNF-α and IL-1β, and consequently to shift towards the non-classic Th1 phenotype make them highly pathogenic in particular micro-environmental conditions. Accordingly, in human clinical trials, anti-IL-17 monoclonal antibody (mAb) therapy revealed variable and mostly modest effects in patients with autoimmune disorders, suggesting that the function of IL-17A in autoimmune disease is context- or tissue-dependent. For example, whereas anti-IL-17 mAb treatment has shown marked benefit in psoriasis, it has shown more modest effects in autoimmune uveitis and rheumatoid arthritis, and it actually exacerbated disease symptoms in patients with Crohn’s disease.75,76 The efficacy of anti-IL-17 mAb in psoriasis is consistent with the high levels of IL-17A and the low frequency of CD161+ IFN-γ-producing cells observed in affected skin of these patients,52,77 though IL-17A in inflamed skin is produced by both Th17 cells and skin-resident γδ T cells.78 Therefore, interfering with IL-1β, IL-23, TNF-α and IL-12 signalling in Th17 cells during inflammation may be a promising therapeutic approach to reduce their differentiation into ‘pathogenic’ Th17/Th1 and non-classic Th1 cells in patients with autoimmune diseases.

Accordingly, it has been known for many years that the combined neutralization of IL-12 and IL-23 thank to ustekinumab, a mAb that binds with high affinity to the p40 subunit of both cytokines, results in symptom improvement in both psoriasis and Crohn’s disease.79,80 The observation that TNF-α and IL-1β contribute to the shifting of Th17 lymphocytes towards the Th1 subset60,63 indirectly confirms this hypothesis, because inhibitors of IL-1β and/or TNF-α are successfully used in the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, Crohn’s disease, as well as several other inflammatory diseases. On the other hand, the development of therapeutic antibodies targeting the GM-CSF receptor α-chain offers a valuable opportunity to test the importance of GM-CSF in chronic inflammatory disorders, and an early report on treatment of rheumatoid arthritis patients appears in this regard encouraging.81 Finally, the recent discovery of several RORC inhibitors could represent in the future a good opportunity to target the entire CD161+ T-cell lineage, which includes not only Th17 and Th17/Th1 cells, but also non-classic Th1 cells.82

Concluding remarks

The discovery of a third subset of CD4+ Th cells in addition to Th1 and Th2 cells, named as Th17, has revealed the existence of a more complex pathway of adaptive cell-mediated effector immunity, which overlies the classic Th1/Th2 paradigm. However, Th17 has appeared to be a very flexible phenotype, as a result of the easy shifting of these cells in the inflammatory sites to the Th1 phenotype; the activity of pro-inflammatory cytokines, such as IL-12 and TNF-α, particularly in the presence of IL-1β; or the repeated exposure to IL-23. Therefore, it is now clear that there are two different types of Th1 cells, which have been defined as classic and non-classic (Th17-derived), respectively. The consequence of this previously unknown dichotomy is the present awareness that in the inflammatory sites there is a mixture of the two Th1 cell types and it is therefore difficult to understand whether all the previously described pathogenic effects by Th1 cells are the result of the activity of the classic Th1 subset or they represent the result of damage initiated by Th17 cells but maintained, or even amplified, by their non-classic Th1 progeny. The initial studies in this field seem to suggest that non-classic Th1 cells play a more important role than classic Th1, and even Th17 themselves, in the maintenance of chronic inflammation in several autoimmune disorders. Fortunately, classic and non-classic Th1 cells exhibit not only different functional features, but they have also started to become distinguishable because of distinct phenotypic markers, which may allow their recognition and provide help for identifying the best targets for the novel immunotherapeutic strategies of chronic inflammatory, including autoimmune, disorders.

Acknowledgments

The authors’ laboratories are supported by the Italian Ministry of Health (RF-2010-2314610).

Disclosures

The authors have no potential conflicts of interest.

References

  1. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;175:5–14. [PubMed] [Google Scholar]
  2. Del Prete G, De Carli M, Mastromauro C, Biagiotti R, Macchia D, Falagiani P, Ricci M, Romagnani S. Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest. 1991;88:346–59. doi: 10.1172/JCI115300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Parronchi P, Macchia D, Piccinni MP, et al. Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci USA. 1991;146:3413–8. doi: 10.1073/pnas.88.10.4538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol Today. 1991;12:256–7. doi: 10.1016/0167-5699(91)90120-I. [DOI] [PubMed] [Google Scholar]
  5. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchrooo VK. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature. 2006;441:235–8. doi: 10.1038/nature04753. [DOI] [PubMed] [Google Scholar]
  6. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8:639–46. doi: 10.1038/ni1467. [DOI] [PubMed] [Google Scholar]
  7. Annunziato F, Cosmi L, Santarlasci V, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204:1849–61. doi: 10.1084/jem.20070663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Murphy KM, Stockinger B. Effector T cell plasticity: flexibility in face of changing circumstances. Nat Immunol. 2010;11:674–80. doi: 10.1038/ni.1899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Defining the human T helper 17 cell phenotype. Trends Immunol. 2012;33:505–12. doi: 10.1016/j.it.2012.05.004. [DOI] [PubMed] [Google Scholar]
  10. Maggi L, Santarlasci V, Capone M, et al. Distinctive features of classic and nonclassic (Th17 derived) human Th1 cells. Eur J Immunol. 2012;42:3180–8. doi: 10.1002/eji.201242648. [DOI] [PubMed] [Google Scholar]
  11. Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, Romagnani S. Natural killer cell stimulatory factor (interleukin 12, IL-12) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993;177:1199–204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM. Development of TH1 CD4+ T cells through IL-12 production by Listeria-induced macrophages. Science. 1993;260:547–9. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  13. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1:135–45. doi: 10.1038/35100529. [DOI] [PubMed] [Google Scholar]
  14. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol. 2001;19:423–74. doi: 10.1146/annurev.immunol.19.1.423. [DOI] [PubMed] [Google Scholar]
  15. Parronchi P, De Carli M, Manetti R, et al. IL-4 and IFN (α and γ) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. J Immunol. 1992;149:2977–83. [PubMed] [Google Scholar]
  16. Romagnani S. Induction of TH1 and TH2 responses: a key role for the ‘natural’ immune response? Immunol Today. 1992;13:379–81. doi: 10.1016/0167-5699(92)90083-J. [DOI] [PubMed] [Google Scholar]
  17. Brombacher F, Kastelein RA, Alber G. Novel IL-12 family members shed light on the orchestration of Th1 responses. Trends Immunol. 2003;24:207–12. doi: 10.1016/S1471-4906(03)00067-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mackey MF, Barth RJ, Jr, Noelle RJ. The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells. J Leukoc Biol. 1998;63:418–28. doi: 10.1002/jlb.63.4.418. [DOI] [PubMed] [Google Scholar]
  19. Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell. 2004;117:515–26. doi: 10.1016/s0092-8674(04)00451-9. [DOI] [PubMed] [Google Scholar]
  20. Liotta F, Frosali F, Querci V, et al. Human immature myeloid dendritic cells trigger a TH2-polarizing program via Jagged-1/Notch interaction. J Allergy Clin Immunol. 2008;121:1000–5. doi: 10.1016/j.jaci.2008.01.004. [DOI] [PubMed] [Google Scholar]
  21. Rengarajan J, Szabo SJ, Glimcher LH. Transcriptional regulation of TH1/TH2 polarization. Immunol Today. 2000;21:479–83. doi: 10.1016/s0167-5699(00)01712-6. [DOI] [PubMed] [Google Scholar]
  22. Bonecchi R, Bianchi G, Bordignon PP, et al. Differentiual expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med. 1998;187:129–34. doi: 10.1084/jem.187.1.129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM. CCR5 is characteristic of Th1 lymphocytes. Nature. 1998;391:344–5. doi: 10.1038/34814. [DOI] [PubMed] [Google Scholar]
  24. Klose CS, Flach M, Mohle L, et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. 2014;157:340–56. doi: 10.1016/j.cell.2014.03.030. [DOI] [PubMed] [Google Scholar]
  25. Mariotti S, Del Prete GF, Mastromauro C, De Carli M, Romagnani S, Ricci M, Pinchera A. The autoimmune infiltrate of Basedow’s disease: analysis of clonal level and comparison with Hashimoto’s thyroiditis. Exp Clin Endocrinol. 1991;97:139–46. doi: 10.1055/s-0029-1211053. [DOI] [PubMed] [Google Scholar]
  26. Windhagen A, Nicholson LB, Weiner HL, Kuchroo VK, Hafler DA. Role of Th1 and Th2 cells in neurologic disorders. Chem Immunol. 1996;63:171–86. [PubMed] [Google Scholar]
  27. Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today. 1995;16:34–8. doi: 10.1016/0167-5699(95)80068-9. [DOI] [PubMed] [Google Scholar]
  28. Quayle AJ, Chomarat P, Miossec P, Kjeldsen-Kragh J, Forre O, Natvig JB. Rheumatoid inflammatory T-cell clones express mostly Th1 but also Th2 and mixed (Th0-like) cytokine patterns. Scand J Immunol. 1993;38:75–82. doi: 10.1111/j.1365-3083.1993.tb01696.x. [DOI] [PubMed] [Google Scholar]
  29. Parronchi P, Romagnani P, Annunziato F, et al. Type 1 T-helper predominante and interleukin-12 expression in the gut of patients with Crohn’s disease. Am J Pathol. 1997;150:823–32. [PMC free article] [PubMed] [Google Scholar]
  30. Moller DR, Forman JD, Liu MC, et al. Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis. J Immunol. 1996;156:4952–60. [PubMed] [Google Scholar]
  31. D’Elios MM, Josien R, Manghetti M, et al. Predominant Th1 cell infiltration in acute rejection episodes of human kidney grafts. Kidney Int. 1997;51:1876–84. doi: 10.1038/ki.1997.256. [DOI] [PubMed] [Google Scholar]
  32. Frostegard J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U, Hansson GK. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 1999;145:33–43. doi: 10.1016/s0021-9150(99)00011-8. [DOI] [PubMed] [Google Scholar]
  33. Benagiano M, D’Elios MM, Amedei A, et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques. J Immunol. 2005;174:6509–17. doi: 10.4049/jimmunol.174.10.6509. [DOI] [PubMed] [Google Scholar]
  34. Romagnani S. Lymphokine production by human T cells in disease states. Annu Rev Immunol. 1994;12:227–57. doi: 10.1146/annurev.iy.12.040194.001303. [DOI] [PubMed] [Google Scholar]
  35. Romagnani S. The Th1/Th2 paradigm. Immunol Today. 1997;18:263–6. doi: 10.1016/s0167-5699(97)80019-9. [DOI] [PubMed] [Google Scholar]
  36. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ. Divergent pro-and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198:1951–7. doi: 10.1084/jem.20030896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Cua DJ, Cua J, Sherlock Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421:744–8. doi: 10.1038/nature01355. [DOI] [PubMed] [Google Scholar]
  38. Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchrooo VK. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med. 2004;200:79–87. doi: 10.1084/jem.20031819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13:715–25. doi: 10.1016/s1074-7613(00)00070-4. [DOI] [PubMed] [Google Scholar]
  40. Veldhoen M, Stockinger B. TGFβ1, a ‘Jack of all trades’, the link with pro-inflammatory IL-17-producing T cells. Trend Immunol. 2006;27:358–61. doi: 10.1016/j.it.2006.06.001. [DOI] [PubMed] [Google Scholar]
  41. Li M, Wan YY, Flavell RA. T cell-produced transforming growth factor-β1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity. 2007;26:579–91. doi: 10.1016/j.immuni.2007.03.014. [DOI] [PubMed] [Google Scholar]
  42. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORct directs the differentiation program of proinflammatory IL-17 T helper cells. Cell. 2006;126:1121–31. doi: 10.1016/j.cell.2006.07.035. [DOI] [PubMed] [Google Scholar]
  43. Yang XO, Pappu BP, Nurieva R, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR α and ROR γ. Immunity. 2008;28:29–39. doi: 10.1016/j.immuni.2007.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Durant L1, Watford WT, Ramos HL, et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity. 2010;32:605–15. doi: 10.1016/j.immuni.2010.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Ye P, Rodriguez FH, Kanaly S, et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulatory factor expression, neutrophil recruitment, and host defense. J Exp Med. 2001;194:519–27. doi: 10.1084/jem.194.4.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28:454–67. doi: 10.1016/j.immuni.2008.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Gutcher I, Becher B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest. 2007;117:1119–27. doi: 10.1172/JCI31720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Tato CM, Laurence A, O’Shea JJ. Helper T cell differentiation enters a new era: le roi est mort; vive le roi ! J Exp Med. 2006;203:809–12. doi: 10.1084/jem.20060522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Chen Z, Tato CM, Muul L, Laurence A, O’Shea JJ. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum. 2007;56:2936–46. doi: 10.1002/art.22866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8:950–7. doi: 10.1038/ni1497. [DOI] [PubMed] [Google Scholar]
  51. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin-17-producing human T helper cells. Nat Immunol. 2007;8:942–9. doi: 10.1038/ni1496. [DOI] [PubMed] [Google Scholar]
  52. Cosmi L, De Palma R, Santarlasci V, et al. Human interleukin-17-producing cells originate from a CD161+ CD4+ T-cell precursor. J Exp Med. 2008;205:1903–16. doi: 10.1084/jem.20080397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Ghoreschi K, Laurence A, Yang XP, et al. Generation of pathogenic TH17 cells in the absence of TGF-β signaling. Nature. 2010;467:967–71. doi: 10.1038/nature09447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Chung Y, Chang SH, Martinez GJ, et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 2009;30:576–87. doi: 10.1016/j.immuni.2009.02.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Santarlasci V, Maggi L, Capone M, et al. Rarity of human T helper 17 cells is due to retinoic acid orphan receptor-dependent mechanisms that limit their expansion. Immunity. 2012;36:201–14. doi: 10.1016/j.immuni.2011.12.013. [DOI] [PubMed] [Google Scholar]
  56. Chu CC, Paul WE. Expressed genes in interleukin-4 treated B cells identified by cDNA representational difference analysis. Mol Immunol. 1998;35:487–502. doi: 10.1016/s0161-5890(98)00031-5. [DOI] [PubMed] [Google Scholar]
  57. Boulland ML, Marquet J, Molinier-Frenkel V, et al. Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation. Blood. 2007;110:220–7. doi: 10.1182/blood-2006-07-036210. [DOI] [PubMed] [Google Scholar]
  58. Santarlasci V, Maggi L, Mazzoni A, et al. IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells. Eur J Immunol. 2014;44:654–61. doi: 10.1002/eji.201344047. [DOI] [PubMed] [Google Scholar]
  59. Cosmi L, Cimaz R, Maggi L, et al. Evidence of the trasnsient nature of the Th17 phenotype of CD4+CD161+ T cells in the synovial fluid of patients with juvenile idiopathic arthritis. Arthritis Rheum. 2011;63:2504–15. doi: 10.1002/art.30332. [DOI] [PubMed] [Google Scholar]
  60. Maggi L, Cimaz R, Capone M, et al. Eternecept inhibits the tumor necrosis factor α-driven shift of Th17 lymphocytes toward nonclassic Th1 phenotype in juvenile idiopathic arthritis. Arthritis Rheumatol. 2014;66:1372–7. doi: 10.1002/art.38355. [DOI] [PubMed] [Google Scholar]
  61. Lexberg MH, Taubner A, Albrecht I, Lepenies I, Richter A, Kamradt T, Radbruch A, Chang HD. IFN-γ and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells. Eur J Immunol. 2010;40:3017–27. doi: 10.1002/eji.201040539. [DOI] [PubMed] [Google Scholar]
  62. Duhen R, Glatigny S, Arbelaez CA, Blair TC, Oukka M, Bettelli E. Cutting edge: the pathogenicity of IFN-γ-producing Th17 cells is independent of T-bet. J Immunol. 2013;190:4478–82. doi: 10.4049/jimmunol.1203172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Duhen T, Campbell DJ. IL-1β promotes the differentiation of polyfunctional human CCR6+CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes. J Immunol. 2014;193:120–9. doi: 10.4049/jimmunol.1302734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Romagnani S. The TH1/TH2 paradigm in disease. Molecular Biology Inteligence Unit. Austin, TX, USA: R.G. Landes Company; 1997. [Google Scholar]
  65. Manetti R, Annunziato F, Tomasevic L, Giannò V, Parronchi P, Romagnani S, Maggi E. Polyinosinic acid: polycytidylic acid promotes T helper type 1-specific immune responses by stimulating macrophage production of interferon-α and interleukin-12. Eur J Immunol. 1995;25:2656–60. doi: 10.1002/eji.1830250938. [DOI] [PubMed] [Google Scholar]
  66. Clerici M. Shearer GM: a TH1 to TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993;14:412–7. doi: 10.1016/0167-5699(93)90208-3. [DOI] [PubMed] [Google Scholar]
  67. Nistala K, Adams S, Cambrook H, et al. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA. 2010;107:14751–6. doi: 10.1073/pnas.1003852107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Kleinschek MA, Boniface K, Sadekova S, et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med. 2009;206:525–34. doi: 10.1084/jem.20081712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Maggi L, Capone M, Giudici F, et al. CD4+ CD161+ T lymphocytes infiltrate Crohn’s disease-associated perianal fistulas and are reduced by anti-TNF-α local therapy. Int Arch Allergy Immunol. 2013;161:81–6. doi: 10.1159/000343467. [DOI] [PubMed] [Google Scholar]
  70. Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, Duquette P, Prat A. Preferential recruitment of interferon-γ-expressing TH17 cells in multiple sclerosis. Ann Neurol. 2009;66:390–402. doi: 10.1002/ana.21748. [DOI] [PubMed] [Google Scholar]
  71. Lee Y, Awasthi A, Yosef N, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol. 2012;13:991–9. doi: 10.1038/ni.2416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12:560–7. doi: 10.1038/ni.2027. [DOI] [PubMed] [Google Scholar]
  73. Piper C, Pesenacker AM, Bending D, Thirugnanabalan B, Varsani H, Wedderburn LR, Nistala K. T cell expression of granulocyte macrophage colony stimulating factor in juvenile arthritis is contingent upon Th17 plasticity. Arthritis Rheumatol. 2014;66:1955–60. doi: 10.1002/art.38647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Ramesh R, Kozhaya L, McKevitt K, Djuretic IM, Carlson TJ, Quintero MA, McCauley JL, Abreu MT. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med. 2014;211:89–104. doi: 10.1084/jem.20130301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Hueber W, Patel DD, Dryja T, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2:52ra72. doi: 10.1126/scitranslmed.3001107. [DOI] [PubMed] [Google Scholar]
  76. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab in Crohn’s disease study group. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomized, double-blind placebo-controlled trial. Gut. 2012;61:1693–700. doi: 10.1136/gutjnl-2011-301668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Harper EG, Guo C, Rizzo H, et al. Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J Invest Dermatol. 2009;129:2175–83. doi: 10.1038/jid.2009.65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Cai Y, Shen X, Ding C, et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity. 2011;35:596–610. doi: 10.1016/j.immuni.2011.08.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, Dooley LT, Lebwohl M. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356:580–92. doi: 10.1056/NEJMoa062382. [DOI] [PubMed] [Google Scholar]
  80. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135:1130–41. doi: 10.1053/j.gastro.2008.07.014. [DOI] [PubMed] [Google Scholar]
  81. Burmester GR, Weinblatt ME, McInnes IB, et al. Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. Ann Rheum Dis. 2013;72:1445–52. doi: 10.1136/annrheumdis-2012-202450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Fauber BP, Magnuson S. Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc) J Med Chem. 2014;57:5871–92. doi: 10.1021/jm401901d. [DOI] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES