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Keywords:

  • Autoimmunity;
  • IL-17;
  • Infection;
  • Innate lymphoid cell;
  • γδ T cell

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. γδ T cells
  5. Innate lymphoid cells
  6. Invariant natural killer T (iNKT) cells
  7. Conclusions
  8. ACKNOWLEDGEMENTS
  9. Conflict of interest
  10. References

The inflammatory cytokine IL-17 plays a critical role in immunity to infection and is involved in the inflammatory pathology associated with certain autoimmune diseases, such as psoriasis and rheumatoid arthritis. While CD4+ and CD8+ T cells are important sources of this cytokine, recent evidence has suggested that γδ T cells and a number of families of innate lymphoid cells (ILCs) can secrete IL-17 and related cytokines. The production of IL-17 by γδ T cells appears to be largely independent of T-cell receptor act-ivation and is promoted through cytokine signalling, in particular by IL-23 in combination with IL-1β or IL-18. Therefore IL-17-secreting γδ T cells can be categorised as a family of cells similar to innate-like lymphoid cells. IL-17-secreting γδ T cells function as a part of mucosal defence against infection, with most studies to date focusing on their response to bacterial pathogens. γδ T cells also play a pathological role in certain autoimmune diseases, where they provide an early source of IL-17 and IL-21, which initiate responses mediated by conventional IL-17-secreting CD4+ T cells (Th17 cells). ILCs lack an antigen receptor or other linage markers, and ILC subsets that express the transcriptional factor RORγt have been found to secrete IL-17. Evidence is emerging that these newly recognised sources of IL-17 play both pathological and protective roles in inflammatory diseases as discussed in this article.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. γδ T cells
  5. Innate lymphoid cells
  6. Invariant natural killer T (iNKT) cells
  7. Conclusions
  8. ACKNOWLEDGEMENTS
  9. Conflict of interest
  10. References

Although early studies suggested that IL-17 was produced primarily by αβ T cells [1, 2], it has recently been found that various “innate” subsets of lymphoid cells can produce this cytokine [3-6]. Indeed the term Th17 cell, which refers to IL-17-secreting CD4+ T cells, does not include CD8+ T cells and γδ T cells, which have been revealed to be high producers of this cytokine [7]. γδ T cells, together with natural killer (NK) cells, NKT cells, and several populations of innate lymphoid cells (ILCs), belong to a family of IL-17-secreting lymphocytes that fits more closely with the innate rather than the adaptive immune system.

The discovery of these innate sources of IL-17 has led to a re-examination of the roles played by effector and pathogenic cells in diseases where IL-17 is implicated, such as bacterial and fungal infection and cancer, as well as in gut homeostasis. In addition, these innate IL-17 producers have been shown to participate in the initiation of autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), arthritis, and colitis [6, 8, 9]. While much of the work identifying and characterizing the function of IL-17-producing γδ T cells and ILCs discussed in this review is based on the studies from mouse models, these cells have also been identified in humans. While there are some differences in repertoire and phenotype of the human IL-17-producing γδ T cells and ILCs as compared with those in the mouse, evidence to date suggests that both cell populations perform the same functions.

γδ T cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. γδ T cells
  5. Innate lymphoid cells
  6. Invariant natural killer T (iNKT) cells
  7. Conclusions
  8. ACKNOWLEDGEMENTS
  9. Conflict of interest
  10. References

γδ T cells account for approximately 3–5% of all lymphoid cells found in the secondary lymphoid tissues and the blood. These cells are the first immune cells found in the fetus and provide immunity to newborns prior to activation of the adaptive immune system [10]. γδ T cells are much more prevalent at mucosal and epithelial sites, especially the gut, where they can account for up to 50% of the total intraepithelial lymphocyte population. Although γδ T cells express a TCR, this TCR does not engage MHC-antigen complexes in the same manner as αβ T cells [11]. Instead, it appears to act more like pattern recognition receptors, recognizing conserved phosphoantigens of bacterial metabolic pathways, as well as products of cell damage [12]. Activation via the γδ TCR in the thymus has, however, been shown to determine the cytokine profile of γδ T cells following their departure from the thymus.

The γδ TCR is comprised of a γ chain, which is located on the same chromosome as the TCR β chain, and a δ chain that is located within the same locus as the TCR α chain. The γδ T-cell field has been hampered by a lack of consensus with regard to nomenclature for the various γ chains. Of the two systems in common use, that of Garman [13] and that of Heilig and Tonegawa [14], we have used the latter throughout this review. While γδ T cells appear to be primarily activated via their TCR, engagement of the TCR is not essential for their activation.

γδ T cells in infection

γδ T cells have been shown to play an important role in the early immune response to a range of infectious agents, including fungi, bacteria, viruses and parasites [15]. This may explain their abundance at mucosal sites, as well as their ability to be rapidly activated following exposure to pathogens or inflammatory cytokines, produced by macrophages or dendritic cells (DCs) in responses to PAMPs. γδ T cells can function in the resolution of infection in a number of ways, including acting as antigen presenting cells (APCs) and promoting recruitment of effector cells to the site of infection. γδ T cells were shown to facilitate bacterial clearance via neutrophil, macrophage, and NK-cell recruitment, as well as contributing to IFN-γ production at the site of infection [15-17]. Similarly, IL-17 had been shown to play a pivotal role in the resolution of bacterial pathogens, especially early in infection. IL-17 has been shown to increase chemokine expression and rapidly induce neutrophil recruitment following Klebsiella pneumonia infection in the lung, and is required for the control of Salmonella enterica enteritidis infection of the gastrointestinal (GI) tract[18, 19].

A study by Lockhart et al. demonstrated that γδ T cells in the lung produce IL-17 following Mycobacterium tuberculosis infection and provided the first crucial evidence linking γδ T-cell activation, neutrophil recruitment, and resolution of infection [20]. Indeed this study demonstrated that despite the relatively low percentage of γδ T cells within the lymphocyte compartment (<5% total lymphocytes), these cells are a more potent source of IL-17 as compared with activated CD4+ T cells, which had previously been identified as the main producers of IL-17. IL-17-producing γδ T cells are also increased in patients with active pulmonary tuberculosis [21]. Further studies using a variety of bacterial models have described crucial roles for IL-17-secreting γδ T cells in the resolution of bacterial infection, including Staphylococcus aureus infection of the skin [22], S. enterica infection in the lung [18], Listeria moncytogenes infection in the liver [23], and intraperitoneal infection with Escherichia coli [24]. The Vδ1 subset of γδ T cells has been shown to be a major source of IL-17 following E. coli infection while human Vδ2+ IL-17+ γδ T cells have been found in the peripheral blood of children with bacterial meningitis [25]. IL-17-secreting γδ T cells have also been described in viral infections [26]. The Vγ4 subset of γδ T cells has been shown to be a major source of IL-17 in Con-A-induced fulminant hepatitis [27], while the Vγ4 subset of γδ T cells has been shown to control RSV and West Nile virus infection [26, 28].

Activation of γδ T cells

Various chemokine receptors, cytokine receptors, and pattern recognition receptors are expressed by γδ T cells and these receptors have been shown to be involved in the activation of γδ T cells, especially for the induction of IL-17 (Fig. 1). IL-1, IL-6, IL-18, IL-23, and transforming growth factor beta 1 (TGF-β) have each been implicated in promoting IL-17 production by γδ T cells. Furthermore, activation via Toll-like receptor 2 (TLR2) and DC-associated C-type lectin 1 (dectin 1), as well as the internal receptor aryl hydrocarbon receptor (AhR), has also been associated with IL-17 production by γδ T cells [30]. However, highly purified γδ T cells do not appear to produce IL-17 following stimulation with TLR agonists in the absence of exogenous cytokines (Sutton, Mielke, and Mills, unpublished data). Furthermore, γδ T cells from IL-6−/− mice produce IL-17 at comparable levels to wild-type mice [31], while ablation of TGF-β leads to a reduction but not a total loss of IL-17, suggesting that there may be a non-essential role for these cytokines in promoting IL-17 production by γδ T cells. In contrast, γδ T cells in a spleen cell preparation from IL-1 type I receptor-defective (IL-1RI−/−) mice fail to secrete IL-17 in response to IL-23 and/or TLR agonists (Sutton and Mills unpublished data). Furthermore, IL-1α or IL-1β in synergy with IL-23, has been shown to play a crucial role in the induction of IL-17 from γδ T cells in both mice and humans [6, 25, 32, 33]. Interestingly, γδ T cells express IL-1RI and have high levels of IL-18R on their cell surface, and it has recently been demonstrated that IL-18 can synergize with IL-23 to promote IL-17 production by γδ T cells [29]. It appears that the activation of the inflammasome in DCs and macrophages, and the consequent processing of the cytokines IL-1β and IL-18, from an inactive precursor to an active form as a result of inflammasome-triggered pathways, is important for the generation of IL-17-secreting γδ T cells [29].

image

Figure 1. Innate IL-17 production by γδ T cells. As well as expressing γδ TCR, γδ T cells express receptors for IL-1, IL-6, IL-18, IL-21, IL-23, and TGF-β. γδ T cells also variably express certain TLRs, especially TLR2, and constitutively express the transcription factor RORγt. The production of IL-23, IL-1 and IL-18 by PAMP (pathogen-associated molecular pattern)/DAMP (danger-associated molecular pattern)-activated innate immune cells (DCs and macrophages), as well as direct activation via the internal receptors AhR and Dectin 1, promotes IL-17 production by γδ T cells in the absence of TCR engagement. This IL-17 production by γδ T cells is associated with upregulated surface receptor expression of CD25, CCR6, CD127, and SCART (scavenger-associated receptor) as well as by STAT3 activation. The transcription factor Notch is associated with the development of IL-17 producing γδ T cells in the thymus; the IL-17-secreting γδ T cell is termed a “γδ17 cell”.

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A defect in the response of IL-17+ γδ T cells, but not IFN-γ+ γδ T cells, to malaria infection has been reported in MyD88-deficient mice [34]. This provides further evidence that activation of TLR (and hence MyD88) signaling and the consequent production of inflammatory cytokines, such as IL-1 (that also signals via MyD88), IL-23, and IL-6, are important steps in driving IL-17 production from γδ T cells. CCR6, the chemokine receptor for CCL20, has been shown to be associated with IL-17+ RORγt+ CD4+ T cells and has also been shown to be present on IL-17+ γδ T cells [30].

IL-2, which has been shown to constrain Th17-cell differentiation [35], appears to have a role in inducing IL-17 production from γδ T cells. Indeed, the IL-2 receptor α chain (CD25), but not the IL-2 receptor β chain (CD122), has been shown to be expressed on the surface of IL-17-producing γδ T cells [36]. However, IL-17-producing γδ T cells have been detected in both IL-2- and CD25-deficient mice, indicating that IL-2 may play a role in maintenance rather than induction of IL-17-producing γδ T cells. However, there may also be an antagonistic role for IL-2 with regard to IL-17-producing γδ T cells, as IL-2 is a potent inducer of IFN-γ that can suppress IL-17 production by CD4+ T cells. In contrast, the IL-2 homologue, IL-21 has been shown to augment IL-17 production by γδ T cells and this may reflect the fact that IL-21 does not promote IFN-γ production [12].

Signaling pathways regulating IL-17 production by γδ T cells

The transcription factors retinoic acid-related orphan receptor (ROR) γt and signal transducer and activator of transcription 3 (STAT3) have been associated with IL-17 production from both αβ T cells and activated γδ T cells [1]. Interestingly, there appears to be a higher constitutive expression of RORγt in γδ T cells as compared with other T cells [6]. Furthermore, RORγt-deficient mice have a defect in IL-17 production [1]. However, it should be noted that RORγt expression is not confined to IL-17-producing cells, indicating that this is not the only transcriptional factor involved in IL-17 production [38]. In contrast, the PU.1 transcription factor has been shown to negatively regulate proliferation and IL-17 production by γδ T cells [39].

Thymic development of IL-17-producing γδ T cells

γδ T cells are capable of IL-17 production prior to exiting the thymus [36]. This intrathymic IL-17 production has recently been ascribed to Notch signaling and activation of the Hes1 protein [40], rather than to the actions of STAT3 and RORγt. Activation of γδ T cells via their TCR in the thymus appears to dictate the cytokine profile of these cells, with the strength of antigen binding dictating the response. It has been reported that thymic γδ T cells that are antigen-naïve or bind antigen with low affinity, produce IL-17, while antigen-experienced γδ T cells that bind antigen with high affinity produce IFN-γ [41]. This observation was confirmed and extended by a recent study showing that Skint-1, a molecule expressed by thymic and epidermal epithelial cells, activates Egr3 which, in turn, promotes differentiation of IFN-γ-secreting γδ T cells and suppresses development of RORγt+ IL-17-secreting γδ T cells [42].

The TNF receptor family member CD27 is required for the development of IFN-γ-producing antigen-primed γδ T cells, but not antigen-naïve IL-17-producing γδ T cells, emerging from the thymus. Indeed CD27 γδ T cells have been shown to express RORγt (Th17-lineage transcription factor), while CD27+ γδ T cells express Tbet (Th1-lineage transcription factor) [34]. Other cell surface receptors have also been associated with IL-17 production from γδ T cells, including CD127 (IL-7R), CCR6, and the scavenger receptor SCART [43, 44].

γδ T cells in autoimmunity

A number of studies, mainly in mouse models, have shown that Th17 cells and IL-17 play a pathogenic role in the development of various autoimmune diseases, including EAE, inflammatory bowel disease (IBD), inflammatory skin diseases, and collagen-induced arthritis (CIA), as well as graft-versus-host disease [7, 45, 46]. Using a murine model for psoriasis, it has recently been shown that IL-23-activated dermal γδ T cells are the major source of IL-17 in the skin [47]. It has also been reported that γδ T cells may have a pathogenic role in the development of EAE as TCRδ−/− mice have reduced disease severity in the EAE model, especially in the later disease stages [48, 49]. Furthermore, in an adoptive transfer model of EAE, depletion of γδ T cells reduced the severity and delayed the onset of disease [6] [50]. In addition, IL-17-secreting γδ T cells have been shown to accumulate in the brains of mice with EAE [6, 51]. IL-17-producing γδ T cells have also been implicated in the pathology of CIA and uveitis [6, 9, 52]. In both CIA and EAE, the Vγ4 subset of γδ T cells has been shown to be the major source of IL-17, and this IL-17-producing population accumulates in the brains of mice with EAE and in the draining lymph nodes of mice with CIA [6, 9]. As well as contributing to the pool of IL-17 during the development of autoimmunity, IL-17 and IL-21 production by γδ T cells may also help to initiate or augment IL-17 production by αβ T-cell activation, thus γδ T cells may act to prime Th17-cell responses [37].

Although much of the evidence to date suggests that γδ T cells have a pathogenic role in autoimmunity, it has also been shown that intraepithelial γδ T cells play a protective role in dextran sodium sulfate (DSS)-induced colitis by preserving the integrity of the intestinal epithelium [53] although the mechanistic explanations for these different roles are currently unknown.

γδ T cells in antitumor immunity

The role of IL-17 in antitumor defence is still unclear, with evidence of both pro- and antitumor effects. γδ T cells are one of the most important sources of IL-17 production induced by dying tumor cells during chemotherapy [32]. It has been shown, as discussed above, that IL-1 plays a crucial role in stimulating IL-17 production by γδ T cells and it has also been shown that IL-1-driven γδ T-cell IL-17 production plays a role in antitumor immunity [32]. Furthermore, TCRδ−/− and Vγ4/Vγ6−/− mice have a significant reduction in their ability to respond to chemotherapy. γδ T-cell IL-17 production was found to be essential for the control of tumor growth via chemoattraction of CD8+ T cells and subsequent CD8+ T-cell IFN-γ production [32].

The ability of γδ T cells to act in an APC-like manner has been exploited in their use as immunotherapeutics for cancer. The aim of cancer immunotherapy is to overcome immunosuppression at the site of the tumor by skewing the cytokine repertoire in favor of proinflammatory responses. Ex vivo activated γδ T cells have been shown to control tumor growth [54]. Various stimuli have been examined for their ability to promote γδ T-cell activation, including HMB-PP, zoledronate, IL-18, IL-2, and the anti-γδ TCR antibody GL3 [54-56]. Indeed, clinical trials with activated γδ T cells have shown promising results for the treatment of solid tumors [57], lymphoma [54], renal carcinoma [58], and lung cancer [55].

Human γδ T cells

Humans have a less varied repertoire of γδ T cells as compared with mice; indeed, the majority of human γδ T cells are of either the Vδ1+ or Vδ2+ subclasses of γδ T cells. The majority of human peripheral blood γδ T cells are of the Vδ2+ subset, while the Vδ1+ cells account for the bulk of γδ T cells found at the epithelium. Similar to the murine γδ TCR, the human γδ TCR has been shown to be activated in an MHC-independent manner. Vγ9Vδ2+ T cells are rapidly activated by (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) and to a lesser extent by isopentenyl pyrophosphate (IPP), both metabolites of the isoprenoid biosynthesis pathway in bacteria and protozoa [59-62]. Furthermore, neonatal Vγ9Vδ2+ T cells produce IL-17, but not IFN-γ, following stimulation with IL-23 and the aminobisphosphonate zoledronate [60]. In addition, it has been demonstrated that combinations of IL-1, IL-23, IL-6, and TGF-β promote IL-17 production from RORγt+ Vγ9Vδ2+ T cells [25, 63-65]. Of note, mice do not appear to express a homologue of the Vγ9Vδ2 TCR. Other stimuli for human γδ T cells are zoldronate, IL-2, IL-18, and anti-γδ TCR antibodies [54-56, 66]. The anti-γδ TCR antibody GL3 appears to induce more sustained proliferation of both Vδ2 and Vδ1 human γδ T cells than phosphoantigen-expanded human γδ T cells [54].

Innate lymphoid cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. γδ T cells
  5. Innate lymphoid cells
  6. Invariant natural killer T (iNKT) cells
  7. Conclusions
  8. ACKNOWLEDGEMENTS
  9. Conflict of interest
  10. References

ILCs develop from hematopoietic precursors and have common phenotypic characteristics with T lymphocytes, yet they lack expression of specific antigen receptors (Fig. 2). All ILCs depend on IL-7 for their development. Evidence is emerging that these cells differentiate into subsets capable of producing effector cytokines similar to the different T helper cell subsets, except it appears that ILCs are able to respond more rapidly to inflammatory stimuli (as reviewed in [67]). ILCs are a heterogeneous population of cells, often increased in number at barrier surfaces, where they play a protective role in immune responses to infection [68]; however, there is emerging evidence that dysregulation of the IL-17-producing ILC subset drives intestinal inflammation, leading to colitis [3].

image

Figure 2. Lineage relationship and phenotype of IL-17-producing ILCs. All ILC subsets, including NK cells, developed from precursors dependent on the transcriptional repressor Id2. The RORγt-expressing ILC subsets are the main source of IL-17 and all depend on RORγt for their development, which indicates that they are derived from a common precursor. Fetal LTi cells and adult LTi-like cells, which can express CD4, have been shown to secrete IL-17, IL-22 or both. Mouse NKR-LTi cells predominantly secrete IL-22, but the human equivalents have been shown to also produce IL-17. Sca-1-expressing ILCs produce both IL-17 and IFN-γ, and recent evidence suggests that they play a critical role in driving inflammation in the intestine leading to colitis.

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Id2 (inhibitor of DNA binding-2) is a helix-loop-helix transcription factor that lacks DNA-binding domains and heterodimerizes with E-box proteins to act as a critical regulator of gene transcription [69]. It is a key regulatory protein essential for a wide range of developmental and cellular processes and is essential for the development of all ILC subsets [70-72]. In addition to Id2, a number of other transcription factors have been reported to control ILC development and cell phenotype, and expression of these transcription factors can be used to group ILCs into three functionally distinct categories:

  1. Type 1 ILCs (ILC1, NK cells, or cytotoxic ILCs) that depend on thymocyte selection-associated HMG box protein (TOX) for their development and have the ability to kill target cells and produce IFN-γ [73];
  2. Type 2 ILCs (nuocytes, natural helper cells) that depend on RORα for their development [74] produce Th2-associated cytokines (e.g. IL-5 and IL-13), and play a critical role in immune responses to parasitic worm infection [75-77]. These type 2 ILCs have not been shown to produce IL-17;
  3. RORγt± ILCs that include fetal lymphoid tissue inducer (LTi) cells and adult LTi-like cells. Fetal LTi cells are essential for initiating development of lymph nodes and Peyer's patches [71, 78-80]. Adult LTi-like cells are present after birth and initiate development of cryptopatches and lymphoid follicles in the small and large intestine. LTi-like cells are also present at a lower frequency in the spleen and lymph nodes [5]. It is thought that these cells help to maintain and repair secondary lymphoid tissues in response to infection and inflammation [81]. Since the identification of RORγt as a critical transcription factor essential for IL-17 production by Th17 cells, numerous reports have shown that RORγt+ ILCs also produce IL-17 [3, 82, 83].

IL-17-producing RORγt+ ILCs

Type 1 and type 2 ILCs do not express RORγt; however, RORγt plays an important role in the differentiation and maintenance of the third type of ILCs, which includes LTi and LTi-like cells, as these cells constitutively express RORγt [84-86]. RORγt+ ILCs can be further divided into at least three different subsets: (i) classical LTi-like ILCs, (ii) Sca-1+ ILCs and, (iii) NKR-LTi cells. Classical LTi-like ILCs are defined as lineage negative (CD3CD19NK1.1NKp46Gr.1CD11c) CD45+c-kit+IL-7R+ and around 50% of these cells in mice express CD4 [87]. Both mouse and human LTi cells constitutively express IL-17 in the intestine in the developing fetus [82, 88] and studies in mice have shown that when microbial colonization occurs after birth secretion of IL-17 by LTi-like cells begins to decrease and is not detectable by 8 weeks of age. Sca-1+ ILCs have been identified in mice and are nonclassical intestinal LTi-like ILCs that are lineage negative RORγt+IL-7R+CCR6+, but unlike LTi cells, they are Sca-1+c-kitCD4 [3]. These Sca-1+ ILCs have been shown to secrete both IL-17 and IFN-γ upon stimulation with IL-23 [3].

NKR-LTi cells are characterized by their expression of NK cytotoxicity receptors: NKp46 in mice and NKp44 in humans. These NKR-LTi cells have been identified in the intestine and tonsils in humans [82], and in mice these cells exist in the small intestine, large intestine, and Peyer's patches, and at lower frequencies in the mesenteric lymph nodes [5]. NKR-LTi cells constitutively secrete IL-22, but have also been shown to produce IL-17 in humans. IL-22 production is further enhanced by stimulation with IL-23 alone or with IL-1β [5, 89-92]. Originally thought to represent a subset of NK cells, NKR-LTi cells were also called NK22 cells [89]; however, recent studies have suggested that NK22 cells do not possess cytotoxic NK functions and are developmentally related to LTi cells [5, 93, 94]. Therefore, NK22 and NKR-LTi cells are sometimes called ILC22 [73].

Phenotypic and functional analysis of the different ILC subsets suggests significant heterogeneity exists among RORγt+ ILCs. In vitro culture and in vivo transfer experiments have highlighted the developmental plasticity of RORγt+ ILCs. These experiments show that LTi-like cells can upregulate NKp46 expression, it seems that LTi-like cells, rather than conventional NK cells, may be the direct progenitors of NKR-LTi cells [95]. Consistent with this, conventional NK cells do not develop into NKp46+ ILCs or upregulate expression of RORγt following transfer to Rag2−/−Il2rg−/− mice or in vitro culture with OP-9 stromal feeder cells [95]. Interestingly, while RORγt is thought to be a major transcription factor required for IL-17 production, in mice NKR-LTi cells do not produce IL-17. Therefore, additional subset-specific transcription factors must be required for IL-17 production from classical LTi-like, CD4+ LTi-like, and Sca-1+ ILCs and to prevent IL-17 production by NKR-LTi cells.

Functional roles for IL-17-producing RORγt+ ILCs

Although numerous studies have shown that ILCs produce IL-17, there are no mouse models specifically lacking ILCs; therefore, it has been difficult to study the contribution of this innate source of IL-17 in infection, inflammation, and autoimmune disease. IL-17 production is significantly increased by CD4+ LTi-like cells isolated from the spleens of mice treated with zymosan, as compared with production in untreated mice [83]. Zymosan, prepared from the cell wall components of Saccharomyces cerevisiae, includes ligands for TLR2 and C-type lectin receptors, and both types of receptors are expressed by ILCs [5, 96]. However, zymosan also stimulates IL-23 and IL-1β production by DCs, which can drive IL-17 production. These reports suggest that, like Th17 cells, LTi cells may function to defend against fungal infections, although further studies using live pathogen challenge are required to confirm these findings.

Th17 cells are thought to play a pathogenic role in numerous autoimmune diseases and have been implicated in the inflammation and destruction of intestinal barrier function leading to the development of IBD (Fig. 3). IL-17 production by ILCs has also been shown to induce similar symptoms in mice. Infection of Rag-deficient mice, which lack both T and B cells, with Helicobacter hepaticus induces colitis, which is dependent on IL-23-induced IL-17 and IFN-γ [3]. Sca-1+ ILCs were found to be the innate source of IL-17 and IFN-γ capable of causing colitis. These cells were markedly increased in the lamina propria of infected mice and their depletion with an anti-Thy1 antibody led to abrogation of disease. The pathogenic role of Sca-1+ ILCs was confirmed in a second model. Treatment of Rag-deficient mice with anti-CD40 mimics T cell-DC interactions and induces systemic and tissue-specific inflammation [97]. Similar to the Helicobacter model, IL-23 was responsible for inducing IL-17 production and colon-specific tissue inflammation, and depletion of the Sca-1+ ILCs prevented development of colitis [3].

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Figure 3. Regulation and function of IL-17-producing ILCs in the intestine. LTi-like and NKR-LTi cells spontaneously produce IL-22 in steady state conditions to enhance secretion of antimicrobial factors and maintain barrier function in the intestine. In response to inflammatory stimuli or epithelial cell damage, bacteria penetrate the intestinal epithelial barrier and activate TLRs expressed by DCs, inducing IL-23 production. Sca-1+ ILCs proliferate and produce IL-17 in response to this inflammatory stimuli, leading to the recruitment of myeloid cells and the development of colitis.

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The idea that IL-17 production by ILCs can contribute to autoimmune disease has also been explored in humans. IL-17-producing cells are increased in the intestine of patients with ulcerative colitis and Crohn's disease [8]. CD3 cells contributed significantly to the production of IL-17, both IL-17a and IL-17f mRNA transcripts were increased in CD3 cells isolated from the intestines of patients with IBD as compared with transcripts in healthy controls [8]. In addition, there is an increased frequency of ILCs in the colon and ileum of patients with Crohn's disease but not ulcerative colitis [8]. However, since the absolute numbers of IL-17-producing ILCs in the inflamed intestine are very small, it is still unclear whether these cells play a direct role in driving IBD. Therefore, further studies are needed to determine their exact role.

NK cells (ILC1)

There have been a small number of reports showing that NK cells produce IL-17. Since human NKR-LTi cells have been shown to secrete IL-17 [82], careful analysis and interpretation of the results are essential to avoid confusion between IL-17 production by NKR-LTi cells and that by classical NK cells. In the steady state, NK cells in the spleen do not express RORγt [5]; however, upon infection with Toxoplasma gondii, splenic NK cells have enhanced RORγt expression and secrete IL-17 [4]. A recent report has also shown that CD56+CCR4+ human peripheral blood NK cells produce both IL-17 and IFN-γ and express the transcription factors RORγt and Tbet [98]. These cells are not NKR-LTi cells, since the NK cells in this study did not express IL-7R (CD127), nor IL-23R, and since NKR-LTi cells are not thought to exist in human peripheral blood [82, 89].

Invariant natural killer T (iNKT) cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. γδ T cells
  5. Innate lymphoid cells
  6. Invariant natural killer T (iNKT) cells
  7. Conclusions
  8. ACKNOWLEDGEMENTS
  9. Conflict of interest
  10. References

iNKT cells are a subset of T cells that express a semi-invariant TCR that recognizes glycolipids presented by CD1d molecules expressed on APCs. There have been a number of recent reports demonstrating that iNKT cells play a role in host protection against infection via the production of IL-17. Expression of RORγt in developing iNKT precursor cells is associated with the development of a preprogrammed IL-17-producing subset that does not express NK1.1 [99]. The signals that induce RORγt expression in iNKT precursors and lineage commitment have not yet been defined. These NK1.1 iNKT cells are capable of secreting IL-17 not only in response to stimulation with the synthetic ligand α-galactosylceramide or its analogue PBS-57, but also following stimulation with natural ligands, including LPS or glycolipids derived from Sphingomonas wittichii and Borrelia burgdorferi [100]. This IL-17-producing NK1.1 subset is present at high frequency in the lung, comprising up to 40% of pulmonary iNKT cells in naïve mice. Mice deficient in iNKT cells have reduced pulmonary neutrophil infiltration in response to intranasal administration of glycolipid α-galactosylceramide [100] and are more susceptible to infection with Streptococcus pneumonia due to reduced trafficking of neutrophils to the lungs [101].

Like γδ T cells, IL-17-producing iNKT cells are also present in the lymph nodes and skin. Furthermore, like γδ T cells, stimulation of iNKT cells with cytokines alone, in particular IL-1β and IL-23, induces innate production of IL-17 [102]. Unlike Th17 cells, IL-6 does not seem to be required for γδ T cell or iNKT IL-17 production [37, 103, 104]. Other inflammatory cytokines, such as IL-18, may also be involved in the induction of IL-17 production by iNKT cells. IL-18 alone or in combination with TGF-β induces IL-17 production from peripheral blood mono-nuclear cells from healthy human donors [105]. In addition, a subpopulation of IL-17-producing iNKT cells has been observed in rhesus macaques after infection with simian immunodeficiency virus and this was associated with increased plasma levels of IL-18 and type I IFN [105].

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. γδ T cells
  5. Innate lymphoid cells
  6. Invariant natural killer T (iNKT) cells
  7. Conclusions
  8. ACKNOWLEDGEMENTS
  9. Conflict of interest
  10. References

Research into IL-17 and related cytokines has significantly enhanced our understanding of the mechanisms of immunity to infection and the dysregulated immune responses that lead to different inflammatory pathologies. From this knowledge, exciting new drug targets for the treatment of autoimmune diseases have evolved. While much of the early focus was on IL-17-secreting CD4+ T cells (Th17 cells), there is a significant body of evidence to suggest that there are other lymphocyte populations that provide an "innate" source of IL-17, including γδ T cells and various populations of lineage negative, RORγt positive, ILCs. These cells appear to function primarily in a defensive capacity against pathogens at mucosal surfaces, providing an early source of IL-17 to recruit neutrophils to the site of infection. Furthermore, γδ T cells and ILCs play a role in pathological inflammatory and autoimmune disease. Further characterization of ILC function may therefore identify important new targets for therapeutic intervention against these diseases.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. Introduction
  4. γδ T cells
  5. Innate lymphoid cells
  6. Invariant natural killer T (iNKT) cells
  7. Conclusions
  8. ACKNOWLEDGEMENTS
  9. Conflict of interest
  10. References

This work was supported by grant funding from Science Foundation Ireland to Kingston Mills (PI grant 06/In.1/B87 and IRC grant 07/SRC/B11440).

Conflict of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. γδ T cells
  5. Innate lymphoid cells
  6. Invariant natural killer T (iNKT) cells
  7. Conclusions
  8. ACKNOWLEDGEMENTS
  9. Conflict of interest
  10. References

Kingston Mills is a co-founder and shareholder in Opsona Therapeutics and TriMod Therapeutics Ltd., start-up companies involved in the development of immunotherapeutics.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. γδ T cells
  5. Innate lymphoid cells
  6. Invariant natural killer T (iNKT) cells
  7. Conclusions
  8. ACKNOWLEDGEMENTS
  9. Conflict of interest
  10. References
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Abbreviation
CIA

collagen-induced arthritis

IBD

inflammatory bowel disease

Id2

inhibitor of DNA binding-2

ILC

innate lymphoid cell

iNKT

invariant natural killer T cell

LTI

lymphoid tissue inducer

ROR

retinoic acid-related orphan receptor

STAT3

signal transducer and activator of transcription 3