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Abstract

Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease of the gastrointestinal tract, and its pathogenesis has not been fully understood. Extensive dysregulation of the intestinal mucosal immune system is critical in the development and progression of IBD. T helper (Th) 17 cells have the characteristics of plasticity. They can transdifferentiate into subpopulations with different functions in response to different factors in the surrounding environment, thus taking on different roles in regulating the intestinal immune responses. In this review, we will focus on the plasticity of Th17 cells as well as the function of Th17 cells and their related cytokines in IBD. We will summarize their pathogenic and protective roles in IBD under different conditions, respectively, hoping to further deepen the understanding of the pathological mechanisms underlying IBD and provide insights for future treatment.

Keywords

cytokines inflammatory bowel disease intestinal fibrosis plasticity Th17 cells

Introduction

Inflammatory bowel disease (IBD) is a nonspecific, chronic inflammatory disease of the intestinal mucosa that mainly includes ulcerative colitis (UC) and Crohn’s disease (CD). At present, the pathogenesis of IBD has not been fully illustrated. Current researches suggest that there is a heritable component in IBD but it is also influenced by the interaction of environmental factors and the immune system. Impaired intestinal epithelial barrier and dysregulated intestinal microbiota cause excessive activation of natural and adaptive immunity.¹ When the adaptive response is dysregulated, excessive CD4⁺ T-cell responses can lead to tissue damage and even chronic autoimmune pathology.² It is generally believed that CD is primarily associated with the T helper cell (Th)1 immune response, while UC is associated with the Th2 immune response.³ However, recent studies have shown that Th17 cells and regulatory T-cells (Tregs) are also involved in the pathogenesis of IBD.⁴

Th17 cells, characterized by high expression of transcription factors retinoic acid-related orphan receptor (ROR)γt and RORα, low expression of transcription factors T-box express in T-cell (T-bet) and GATA binding protein 3 (GATA3), and high expression of chemokine receptor 6 (CCR6), have a strong correlation with both CD and UC.² The number of Th17 cells and the expression of Th17-related cytokines interleukin (IL)-17A, IL-17F, IL-21, IL-22, and IL-23 are increased in both the intestinal mucosa and serum in patients with active IBD compared to those in patients in remission or healthy individuals.^5–8 Notably, IL-17 expression is consistently higher in patients with CD than in patients with UC.⁶ These increases in Th17 cells and related cytokines are associated with disease activity index, endoscopic and histological grading, C-reactive protein, and platelet levels in patients with IBD.⁹ Even pediatric CD is characterized by Th1 in the terminal ileum and Th1/Th17 immune response in the colon, showing elevated IL-6 and IL-1β expression.¹⁰ Furthermore, mice colonized with fecal microbes from patients with IBD showed more severe intestinal inflammation in colitis modeling, accompanied by an increased number of intestinal Th17 cells and Th2 cells.¹¹ These findings suggest that Th17 cells play an important role in IBD. However, in patients with IBD who respond to adalimumab therapy, the number of CD45RO⁺ CD4⁺ T-cells producing IL-17A and IL-21 in the peripheral blood of patients in remission increases by two to three times compared with that in the active phase, indicating that Th17 cells can balance inflammation and maintain intestinal homeostasis.¹² Genome-wide association studies (GWAS) have identified several Th17-related sites that are linked to single nucleotide polymorphisms associated with IBD. These sites include caspase recruitment domain-containing protein 9 (CARD9) and IL12B, which can affect the production of Th17 cells, as well as signal transducer and activator of transcription (STAT) 3, RORC, IL-23R, Janus kinase (JAK) 2, and tyrosine kinase 2 which are involved in the initiation and maintenance of Th17 cell differentiation. In addition, CCR6 is associated with Th17 cell function. The IL-23R locus is particularly significant in UC and CD, as it contributes significantly to the genetic variance. This locus is under Bonferroni-significant balancing selection, indicating a scenario of allele frequency dependence and host–microbe co-evolution.^13–15 Overall, these findings highlight the significant role of Th17 cells in the development of IBD.

Th17 cell is a double-edged sword in the development of IBD. On the one hand, Th17 cells are crucial for the body’s adaptive immune response to microorganisms like bacteria and fungi, contributing to the formation of intestinal immune barriers. Certain effector molecules of Th17 cells can inhibit inflammation or protect against tissue destruction caused by inflammation.² On the other hand, excessive activation of Th17 cells can worsen the pathological changes associated with IBD through various mechanisms.¹⁶ Despite the increasing research on the occurrence, regulation, and plasticity of Th17 cells in IBD, there is still a lack of in-depth knowledge regarding their dual function, interaction with other immune cells, and their specific involvement in the pathogenesis of IBD. In this review, we will summarize the latest research findings in these areas, and comprehensively discuss the double-edged sword role of Th17 cells in IBD, hoping to further deepen the understanding of the pathological mechanisms underlying IBD and provide insights for future treatments.

Differentiation of Th17 cells

First, it is important to understand that there are some differences between human and mouse Th17 cells.^17,18 Human Th17 cells are characterized by the expression of the transcription factor RORC, which is a homolog of mouse RORγt.¹⁹ In addition, human Th17 cells express CD161 which is the homolog of mouse NK1.1. These cells exclusively originate from CD161⁺ precursors found in umbilical cord blood and newborn thymus in response to the combined activity of IL-1β and IL-23. Notably, murine Th17 cells do not express CD161 and originate in response to IL-6, IL-1, and transforming growth factor (TGF)-β.²⁰ However, Hu et al. found marked similarities in the differential gene expression signatures between human interferon (IFN)-γ⁺ versus IFN-γ⁻ Th17 cells and mouse pathogenic versus non-pathogenic Th17 cells through transcriptomic analysis. Therefore, this review will discuss the research progress of Th17 cells in both humans and mice.²¹

Many transcription factors and cytokines are involved in the differentiation of Th17 cells. The complicated process is mediated by the activity of transcription factors RORγt, RORα, interferon regulatory factor 4 (IRF4), basic leucine zipper ATF-like transcription factor (BATF), and other molecules. In mice, TGF-β and IL-6 can induce naïve CD4⁺ T cells to differentiate into Th17 cells.²² But in humans, the differentiation of Th17 cells also requires the participation of IL-1β as well as IL-21 or IL-23.²³ Several pathways such as STAT3, JAK2, and TGF-β-mothers against decapentaplegic homolog (SMAD) 2 and aryl hydrocarbon receptor (AHR) play important roles in this process^24,25 (see Figure 1).

Figure 1.

Differentiation of Th17 cells. The differentiation of Th17 cells is mediated by the activity of transcription factors RORγt, RORα, IRF4, BATF, and other molecules. TGF-β and many other cytokines such as IL-6, IL-21, IL-23, and IL-1β regulate these transcription factors by activating different signaling pathways, thereby inducing differentiation of Th17 cells. Pathways such as STAT3, JAK2, SMAD2, and AHR play an important role in this process.

TGF-β is a critical cytokine involved in the development of Th17 cells. It works through SMAD pathways and upregulates the expression of IL-23 receptor (R).²⁶ TGF-β co-initiates the differentiation of Th17 cells with IL-6 and induces more IL-21R and IL-23R in naïve CD4⁺ T cells. It also co-maintains the differentiated state of Th17 cells with the assistance of IL-21 and IL-23.²⁷ IL-6 inhibits Treg (iTreg) cell differentiation and promotes the production of IL-17A, which is further amplified by IL-1β and tumor necrosis factor (TNF)-α.^28,29 Khor et al.³⁰ found that the dual-specificity tyrosine phosphorylation-regulated kinases 1A (Dyrk1A) acted as a key regulator in the differentiation of Th17 and Treg cells. They demonstrated that harmine, a small molecule inhibitor of Dyrk1A, effectively mitigated colon inflammation in the CD45RBhi transfer model of colitis by suppressing the differentiation of Th17 cells and enhancing the differentiation of Treg cells. The signaling of IL-6, IL-21, and IL-23 is mediated by the JAK2 and STAT3 pathways.³¹ Activated Th17 cells produce IL-21, which supports the development of Th17 cells in an autocrine way through the STAT3 pathway.³² The signaling of IL-1β is mediated by the activation of JAK2, phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt), STAT3, and nuclear factor kappa B (NF-κB), all of which rely on IL-23.³³ In addition, under Th17 polarization conditions, STAT3 and AHR upregulate the expression of Ikaros family zinc finger 3 (Aiolos), which promotes Th17 differentiation by inhibiting the production of IL-2.³⁴

RORγt has a central function in the process of naïve CD4⁺ T-cell differentiation into Th17 cells.²² STAT3 binds to the promoter of the RORC gene to promote the production of RORγt. In cases where RORγ is deleted, TGF-β and IL-6 can induce the expression of RORα, which, in turn, promotes the production of IL-17A through the STAT3 pathway.³⁵ STAT3 can promote the expression of transcription factors RORγt and RORα, which then form a complex and bind together to the promoter of the IL-17A gene. This further enhances Th17 cell differentiation and the expression of Th17-related cytokines.³⁶

Besides RORγt and RORα, the level of IRF4 is also elevated in patients with active IBD. The elevation is associated with increased production of IL-6, IL-17, and IL-22 mRNA. IRF4 binds to the promoter of IL-17, promoting mucosal RORγt and IL-17 expression.³⁷ Monocytes and conventional dendritic cells (DCs), but not monocyte-derived DCs activated by microbial stimuli, initiate Th17 cell differentiation by secreting IL-1β, and inducing RORγt and IRF4 expression, further inducing IL-1R1 expression by IL-6. However, this process can be suppressed by TGF-β and IL-12.^38,39 Ciofani et al.⁴⁰ described an intracellular network that regulated the Th17 specification, where the binding of BATF and IRF4 contributed to the accessibility of the initial chromatin and initiated the transcription procedure with STAT3, then globally adjusted by the lineage-specifying transcription factor RORγt.⁴⁰

Plasticity of Th17 cells in IBD

Factors affecting the plasticity of Th17 cells

Th17 cells can transdifferentiate and express typical cytokines of other lineages through regulating transcription factors or epigenetic modifications. This process is influenced by cytokines, microbial products, metabolites, and the microenvironment, which is called the plasticity of Th17 cells⁴¹ (see Figure 2). In patients with IBD, there is an increase in the number of Th17 cells that have undergone transdifferentiation, suggesting increased plasticity of Th17 cells in IBD.⁴² The expression of RORγt is not stabilized by a positive feedback loop, making it sensitive to changes in the microenvironment. Thus, it allows Th17 cells to transdifferentiate into other Th cell lineages, forming the basis of Th17 cell plasticity.¹⁶ The activator protein (AP)-1 family transcription factor FOS-like antigen 2 (Fosl2) and JunB are key determinants of Th17 cell plasticity. The absence of Fosl2 or JunB leads to a significant reduction in the number of cells producing only IL-17A and increases the plasticity of Th17 cells.^40,43 However, the loss of castor zinc finger 1 (Casz1) or mammalian target of rapamycin C1 (mTORC1) signaling results in reduced plasticity of Th17 cells.^44,45

Figure 2.

Plasticity of Th17 cells. Under different conditions, steady-state Th17 cells can transdifferentiate into IFN-γ⁺ IL-17A⁺ T helper cells and Foxp3⁺ IL-17A⁺ helper T-cells. The plasticity of the transdifferentiation of Th17 cells in the direction of IFN-γ⁺ IL-17A⁺ T helper cells is related to IL-23, IL-1β, and IL-12. IFN-γ⁺ IL-17A⁺ T helper cells are highly pathogenic and highly correlated with the occurrence of IBD. In the presence of TGF-β, Th17 cells can transdifferentiate into IL-10-producing T regulatory type 1 cells with anti-inflammatory activity. In addition to cytokines, dietary components, environmental factors, noncoding RNAs, and epigenetic modifications can also affect the plasticity of Th17 cells.

IL-23 is one of the key promotors of Th17 cells’ transition to a pro-inflammatory state, which is essential for establishing organ-specific inflammation in autoimmunity.⁴⁶ IL-23 enhances the proliferation and accumulation of intestinal Th17 cells and contributes to the emergence of IFN-γ⁺ IL-17A⁺ T helper cells while inhibiting iTreg cell differentiation and IL-10 production in the colon.⁴⁷ In patients with UC, IL-23 may be associated with the transdifferentiation of Th17 cells, leading to increased pathogenicity and prolonged inflammation in the intestine. The analysis of endoscopic biopsies from patients with UC showed a weaker correlation between IL-23 and other Th17 cell-related cytokines or RORγt in inflamed colon tissues, but a stronger correlation between IL-23 and T-bet as well as GATA3. In the high-IL-23-expression group, there was a higher rate of chronic continuous UC and a lower remission rate compared to the low-IL-23-expression group.⁴⁸ Furthermore, the mRNA level of IL-23 also increased in the inflamed intestines of patients with CD, suggesting its involvement in the development of CD.⁴⁹

IL-1β and IL-2 are associated with the transdifferentiation of Th17 cells toward pro-inflammatory and anti-inflammatory directions, respectively. IL-1β inhibits the production of IL-10, while IL-2 induces its production. IL-2 induces IL-10 by activating STAT5 and reducing RORγt expression, which temporarily downregulates IL-17.⁵⁰ These cytokines, which promote Th17 transdifferentiation, are involved in different responses to specific pathogens. Zielinski et al. found that Candida albicans and Staphylococcus aureus were able to induce Th17 to transdifferentiate in different directions. C. albicans-specific Th17 cells produced IL-17A and IFN-γ but not IL-10. S. aureus-specific Th17 cells produced IL-17A and could produce IL-10 upon restimulation. Both IL-6 and IL-23 were also involved in the Th17 transdifferentiation induced by these pathogens.⁵⁰

In addition to cytokines, other factors such as dietary components, environmental factors, noncoding RNAs, and epigenetic modifications can also affect the plasticity of Th17 cells. AHR is a ligand-dependent transcription factor capable of mediating the effects of environmental factors on Th17 cells. Veldhoen et al.⁵¹ found that when mouse-naïve CD4⁺ T cells were induced to differentiate into Th1, Th2, Th17, and iTreg, only the Th17 subset expressed AHR.⁵¹ During Th17 cell development, the AHR activated by the high-affinity ligand significantly increased the proportion of Th17 cells and the production of related cytokines.⁵¹ Various dietary components like vitamin A, vitamin B3, vitamin D, short-chain fatty acids, tryptophan, high-fat diet, high-salt diet, as well as environmental factors such as intestinal microbiota, biological clock system, and oxygen content can affect the plasticity of Th17 cells through AHR.^16,42 Tubbs et al.⁵² found that excess sodium chloride accumulated in the mouse colon and promoted the expression of IL-1β, IL-6, IL-12, and IL-23 in DC cells, thereby aggravating the inflammatory pathology of IL-10-deficient colitis mouse models.⁵² Noncoding RNAs such as miRNAs play an important role in controlling the differentiation of Th cell plasticity and the mutual regulation between Th cell subpopulations.⁵³ Nucleotide-binding oligomerization domain-containing 2 (NOD2) is an intracellular sensor closely related to the pathogenesis of CD. NOD2 upregulated miR-29 in DCs, which downregulated IL-23 by directly targeting IL-12p40 and indirectly targeting IL-23p19. Consequently, this inhibited the plasticity of Th17 cells in the pro-inflammatory direction.⁵⁴ Dicer1-regulated microRNA-183-96-182 cluster (miR-183C) is induced by the IL-6-STAT3 pathway and highly expressed in Th17 cells. miR-183C promoted the expression of IL-1R1 by inhibiting the expression of the transcription factor forkhead box O1 (FOXO1), thus promoting the plasticity of Th17 cells in the pro-inflammatory direction.⁵⁵ SMAD-7 is a negative regulator of TGF-β signaling. In experimental allergic encephalomyelitis (EAE), miR-21 limited the autocrine inhibition of IL-2 by targeting SMAD-7, thus preventing the plasticity of Th17 cells in the anti-inflammatory direction.⁵⁶ In addition, epigenetic modifications such as histone modifications and transcription factor post-translational modifications can fundamentally affect the plasticity of T cells. Monitoring changes in trimethylation of lysine 4 and lysine 27 can provide insights into the potential for plasticity in T-cell subpopulations.⁵⁷

IFN-γ⁺ IL-17A⁺ T helper cells

There is a correlation between Th1 and Th17. In general, Th1 cells produce IFN-γ and participate in cellular immunity within the cell. Th17 cells produce IL-17A, IL-17F, and IL-22 while participating in the resistance of bacteria and fungi outside the cell.⁴² When pathogens invade the body, Th17 cells can transdifferentiate into IFN-γ⁺ IL-17A⁺ T helper cells in the direction of Th1, shifting the focus of the host immune defense from targeting extracellular microorganisms to targeting intracellular microorganisms.⁵⁸

The plasticity of transdifferentiation of Th17 cells to IFN-γ⁺ IL-17A⁺ T helper cells is influenced by IL-23 and IL-12. IL-12 for inducing Th1 cells and IL-23 for inducing Th17 cells share a common subunit, IL-12p40. Their receptors share a common subunit IL12Rβ1 that binds to IL-12p40.⁵⁹ Under the induction of IL-6, Th17 cells activate and produce IL-21. IL-21 then upregulates RORγt and RORα, leading to the expression of IL-12Rβ2 and IL-23R in Th17 precursor cells.⁶⁰ In EAE, IL-23 can induce transdifferentiation of Th17 cells into highly pathogenic IFN-γ⁺ IL-17A⁺ T helper cells without TGF-β signal.⁶¹ IL-12 stimulation of Th17 cells can increase the expression of T-bet and IFN-γ, downregulate the expression of RORγt and IL-17, and transdifferentiate Th17 cells to the direction of Th1.⁵⁸ In the absence of TGF-β, IL-23, and IL-12 inhibit IL-17 expression and enhance IFN-γ production through STAT4 and T-bet-dependent pathways.⁶²

IFN-γ⁺ IL-17A⁺ T helper cells are highly pathogenic and strongly associated with the development of IBD. IFN-γ secreted by these cells can directly affect intestinal permeability by disrupting the tight junction of the epithelium.⁶³ Harbour et al. demonstrated that Th17 cells were able to participate in the pathogenesis of colitis either by transdifferentiating into pathogenic IFN-γ⁺ IL-17A⁺ T helper cells or by supporting the development of classical pathogenic Th1 cells.⁶⁴ Transfer of Th17 cells into immunodeficient mice was able to induce the occurrence of colitis but these cells have been shown to transdifferentiate into the direction of Th1 in vivo, thus exerting their pathogenic effects.⁶² In patients with IBD, IFN-γ⁺ IL-17A⁺ T helper cells are specifically enriched in inflamed mucosal tissues and may play an important role in the pathogenesis of IBD.⁸ In patients with CD refractory to anti-TNF therapy, IL-17A, IL-23R, and IL-23p19 of the intestinal mucosa were significantly upregulated, but not in responders. Under the influence of IL-23, CD4⁺ TNF receptor 2 (TNFR2)⁺ IL-23R⁺ T-cells were significantly expanded in non-responders to anti-TNF therapy, and these cells had dual IFN-γ⁺ and IL-17A⁺ phenotypes.⁶⁵ Similarly, a specific subset of IFN-γ⁺ IL-17A⁺ Th17 cells in humans (CCR6⁺CXCR3^hiCCR4^loCCR10⁻CD161⁺) was able to stably express P-glycoprotein/multi-drug resistance type 1 (MDR1), became more pro-inflammatory when stimulated by IL-23, and showed resistance to multiple glucocorticoids in vitro.⁶⁶ These findings suggest that IFN-γ⁺ IL-17A⁺ T helper cells may contribute to treatment resistance in patients with IBD, and targeting IL-23 therapy could potentially alleviate these resistances.

Foxp3⁺ IL-17A⁺ T helper cells

Foxp3⁺ IL-17A⁺ helper T-cells are a specific type of cells that express both IL-17A and IL-10. These cells are not produced by the thymus gland, but rather in peripheral organs through differentiation from naïve T cells or transdifferentiation from Th17 or Treg cells.⁶⁷ In mice, an increase in TGF-β concentration is associated with elevated Foxp3 and decreased IL-23R.²⁸ When TGF-β is present, Th17 cells can transdifferentiate into IL-10-producing T regulatory type 1 cells with anti-inflammatory properties, and the activation of AHR supports this process.^68,69 In addition, IL-1β can transdifferentiate Treg cells into Foxp3⁺ IL-17A⁺ T helper cells in vitro by inhibiting the suppressor of cytokine signaling 3 (SOCS3), a negative regulator of NF-κB, thereby increasing the amplitude and duration of STAT3 phosphorylation, and altering STAT3/STAT5 balance.⁷⁰

Foxp3⁺ IL-17A⁺ T helper cells show effective inhibitory activity in vitro coculture systems. These cells secrete IL-17, IL-22, and IL-21, and express high levels of CCR6, CD161, and RORγt. Compared to conventional Th17 cells, they express higher levels of CD101 and lower levels of CD127.⁷¹ Foxp3⁺ IL-17A⁺ T helper cells in the intestinal lamina producing less IL-17 than conventional Th17 cells.²⁸ Esplugues et al. demonstrated that Th17 cells in the small intestine spontaneously limited the pathogenicity of Th17 cells by undergoing phenotypic transformation to express more IL-10, thereby contributing to the regression of inflammation.⁷² However, the number of Foxp3⁺ IL-17A⁺ T helper cells in the peripheral blood and inflamed intestinal mucosal tissues significantly increased in patients with IBD compared to that in healthy individuals.⁷³ Meanwhile, the ability of Treg cells to inhibit T-cell proliferation in IBD decreased by about 60%, which may be related to the increase in Foxp3⁺ IL-17A⁺ T helper cells.⁷⁴ In summary, Foxp3⁺ IL-17A⁺ T helper cells may play a key role in antimicrobial defense and in controlling autoimmunity and inflammation. However, it is difficult to judge whether this subpopulation of Th17 cells has a pathogenic or protective role in IBD.

IL-17⁺ CD8⁺ T cells

There are also IL-17⁺ CD8⁺ T cells (Tc17) that can express IL-17 in the CD8⁺ T-cell subset, which is functionally similar to conventional Th17 cells. Tc17 cells are characterized by high levels of CD6 and CD39, and low levels of CD69, PD-1, and CD27.⁷⁵ Compared with healthy individuals, there was a significant increase in Tc17 cells in peripheral blood and colon tissues in patients with IBD. Furthermore, there was an increase in IFN-γ⁺ IL-17A⁺ CD8⁺ cells in the peripheral blood of patients with IBD and an increase in Foxp3⁺ IL-17A⁺ CD8⁺ T cells in the peripheral blood of patients with CD. However, there is no correlation between the increase in these subpopulations and the clinical activity of IBD.⁷⁶ In vitro experiments have shown that targeting CD6 reduced pro-inflammatory Tc17 and Th17 cells, as well as the production of IL-17, IFN-γ, and TNF.⁷⁵

Pathogenic roles of Th17 cells in IBD

Migration of Th17 cells in IBD

In IBD, Th17 cells differentiate and exhibit autoreactivity, exerting their pathogenic roles by migrating to the intestine and causing inflammation (see Figure 3). When the body is infected by microorganisms and becomes inflamed, the apoptosis of the infected host cells enables major histocompatibility complex (MHC) II in the inflammatory environment to present autoantigens. It induces the differentiation of autoreactive Th17 cells, thereby triggering autoinflammation and autoantibody production.⁷⁷ CCR6 on the surface of Th17 cells facilitates the cells to migrate from mesenteric lymph nodes to inflamed intestinal regions with the assistance of CCR6 ligand chemokine (C-C motif) ligand (CCL) 20.⁷⁸ In addition, IL-17A and IL-17F induce the expression of CCL20 in intestinal epithelial cells (IECs), further promoting the migration of Th17 cells through the CCL20/CCR6 axis.⁷⁴ Th17 cells can also recognize mucosal localization cell-binding molecule-1 (MAdCAM-1) expressed on the intestinal endothelium and venules and migrate to the intestinal mucosal lamina through α4β7 integrin interaction with MAdCAM-1.⁷⁹ Some studies have found that intestinal Th17 cells could be excreted from the intestine in a sphingosine-1 phosphate receptor (S1PR)-dependent manner and migrated to the kidneys via the CCL20/CCR6 axis, causing autoimmune kidney disease. In certain autoimmune settings, intestinal Th17 cells may cause non-intestinal autoimmune diseases by migrating to other target organs.⁸⁰ One study showed that pathogenic Th17 cells in patients with chronic colitis were able to migrate into the brain, resulting in brain inflammation and neurobehavioral disorders, such as multiple sclerosis, ischemic brain injury, and Alzheimer’s disease.⁸¹

Figure 3.

Different roles of intestinal Th17 cells in inflammatory and homeostatic environments. (a) Inflammatory environments: APCs in the inflammatory environments can present autoantigens through MHCII, and induce the differentiation of autoreactive Th17 cells. Th17 cells participate in the development of IBD by secreting cytokines such as IL-17A, IL-17F, IL-21, and TNF-α. Th17 cells promote the recruitment of neutrophils, and the Th17/IL-17 immune response has a pro-fibrotic effect. (b) Homeostatic environments: SFB are key factors driving the development of steady-state tissue-resident Th17 cells in the gastrointestinal tract. Th17 cells maintain intestinal barrier homeostasis and exert a protective role in IBD through IL-17A and IL-22.

Th17 cells and the related pathogenic cytokines

Th17 cells participate in the development of IBD by secreting cytokines such as IL-17A, IL-17F, IL-21, and TNF-α. IL-17A has strong pro-inflammatory activity, and its signaling pathway first requires the recruitment of the adapter NF-κB Activator 1 (Act1). Then several downstream signaling pathways are activated, including NF-κB, mitogen-activated protein kinase (MAPK), and CCAAT-enhancer-binding proteins pathways. These signal transductions cause gene expression of antimicrobial peptides, pro-inflammatory chemokines, and cytokines, as well as matrix metalloproteinase (MMP) by recruiting transforming growth factor kinase 1 and E3 ubiquitin ligases TNF receptor-associated factor 6 (TRAF6).⁸² Excessive IL-17A in the mucosa leads to increased secretion of MMP3 and MMP13 by myofibroblasts, causing damage to epithelial cells by penetrating the extracellular matrix.⁸³ In human intestinal organoids derived from adult stem cells, IL-17A induces caspase 1 (CASP1)-mediated pyroptosis in intestinal stem cells and IECs.⁸⁴ IL-17A can also stabilize the mRNA of TNF-α-induced genes, enhance the IL-8 and TNF-α responses of epithelial cell lines to lipopolysaccharides in vitro, and synergistically exacerbate IBD inflammation with TNF-α.^49,85,86 IL-17A, TNF-α, and IL-22 work together to stimulate IL-17C expression in colonic epithelial cells in an NF-κB-, p38-, and AP-1-dependent manner, forming a novel inflammatory amplification loop in the gastrointestinal tract between epithelial cells and Th17 cells.⁸⁷ Similar to IL-17A, IL-17F can also induce the expression of pro-inflammatory chemokines and cytokines, and MMPs in vitro by IL-17 receptor A (IL-17RA), Act1, and TRAF6. Interestingly, IL-17F deficiency could lead to a reduction in dextran sulfate sodium (DSS)-induced colitis, while IL-17A knockout mice developed more severe intestinal inflammation. Therefore, IL-17A might play a protective role in DSS-induced intestinal inflammation, while IL-17F might exacerbate inflammation.⁸⁸ The failure of human anti-IL-17A monoclonal antibody secukinumab in the therapy of CD may likewise indicate that IL-17A has a protective role.⁸⁹ In a case report study, a patient with treatment-refractory chronic plaque psoriasis developed new-onset Crohn’s-like colitis after a 12-week induction period with Ixekizumab, an anti-IL-17A neutralizing antibody.⁹⁰ This case suggests that certain patient populations, who have both a genetic predisposition and pathogenic microbiome, may be at risk for developing de novo IBD when IL-17A is inhibited. In mice, IL-17R deficiency has shown a highly protective effect against acute colitis induced by trinitrobenzene sulfonic acid (TNBS) possibly by blocking the pro-inflammatory effects of IL-17F.⁹¹ IL-21 has been found to upregulate the expression of genes associated with innate immunity and Th1 responses, such as IFN-γ, T-bet, IL-2Rα, IL-12Rβ2, IL-18R, and myeloid differentiation factor 88 (MyD88). It can also promote STAT3, JAK1, and JAK3 tyrosine phosphorylation, or enhance IL-12-induced STAT4 activation.⁹² In patients with quiescent UC, higher levels of IL-17A, IL-17F, and IL-21 in the colonic mucosa have been associated with increased rates of future relapse, suggesting an underlying immune dysregulation during quiescence.⁹³

Th17 cells promote the recruitment of neutrophils

Th17 cells promote the recruitment of neutrophils, which infiltrate and exert pathogenic effects in the inflamed intestine, thereby aggravating intestinal inflammation. Th17 cells can recruit neutrophils by IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, and IFN-γ, and also can directly chemically recruit neutrophils by releasing biologically active chemokine (C-X-C motif) ligand (CXCL) 8.⁹⁴ IL-17 and TNF-α further enhance the expression of T-cell chemokines CXCL9, CXCL10, and CCL5, as well as neutrophil chemokines CXCL1, CXCL2, and CXCL5, leading to an increase in the expression of P-selectin, E-selectin, integrin ligand intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). These molecular changes ultimately enhance T-cell function, promote in vivo neutrophil transendothelial migration, and enhance neutrophil chemokine (C-X-C motif) receptor (CXCR)2-dependent functions, thereby facilitating the influx of neutrophils into the inflamed areas.⁹⁵ The infiltration of neutrophils in the intestine can prolong the inflammatory response by activating various effects, including phagocytosis, chemotaxis, release of neutrophil extracellular traps (NETs), and production of reactive oxygen species.^96,97 On the one hand, it can promote mucosal healing and the regression of inflammation by engulfing pathogenic microorganisms. On the other hand, it can also lead to damage to the structure of the intestinal mucosa, the epithelial barrier, and the production of inflammatory mediators.⁹⁸ Elevated levels of NETs in tissue and serum samples from both patients with active IBD and experimental colitis exacerbate colon tissue damage and accelerate thrombosis and platelet activation.⁹⁹ In addition, NETs activate T cells through histones. The differentiation of Th17 cells is specifically enhanced by activating STAT3 and RORγt with histone binding to Toll-like receptor 2.¹⁰⁰ IL-23-producing CXCR1⁺ CXCR2⁺ neutrophils, which are the main source of IL-23, can infiltrate and accumulate in the inflamed colonic tissue of IBD. As a result, IL-23 becomes an important initiator of the pathogenic role of Th17 cells.¹⁰¹

Th17 cells promote pathological intestinal fibrosis

In IBD, about 40% of CD patients and 5% of UC patients will develop significant intestinal fibrosis. Fibrosis can cause intestinal stenosis or even intestinal obstruction requiring surgical intervention in about one-third of CD patients.¹⁰² The pathological process of fibrosis involves a shift from physiological repair to pathological fibrosis and from a self-limiting process to a persistent process.¹⁰³ Among them, the production of type I–III collagen is a feature of physiological repair of tissue damage, while the production of type IV, VI, and tenascin collagen indicates the pathological accumulation of fibrosis. In a healthy intestine, the predominant collagen subtypes are type I (70%) and type III (20%). However, in cases of intestinal fibrosis and bowel stenosis in CD, there is an overall increase in collagen content, particularly in subtypes IV, V, and VI.¹⁰⁴

Th17/IL-17 immune response has a pro-fibrotic effect.¹⁰³ IL-17A in the narrow intestine of CD patients has been reported to be significantly overexpressed compared to that in non-narrow regions. This overexpression inhibits myofibroblast migration and upregulates tissue inhibitors of MMP-1, MMP-3, MMP-12, and collagen produced by myofibroblasts in narrowed CD tissues.¹⁰⁵ IL-17 also induces the expression of nuclear factor of κ light polypeptide gene enhancer in B-cell inhibitor, ζ(NFKBIZ) as well as pro-inflammatory chemokines CXCL1 and CXCL6 in the intestinal myofibroblast of patients with CD. This may affect myofibroblast activity and neutrophil chemotaxis.¹⁰⁶ IL-17A-induced expression of heat shock protein 47 is involved in the expression of collagen I in intestinal subepithelial myofibroblasts and contributes to the process of intestinal fibrosis in CD.¹⁰⁷ In addition, IL-17A can induce epithelial–mesenchymal transition and reduce E-cadherin expression, thereby promoting the initiation and development of intestinal fibrosis.¹⁰⁸ IL-17 and IL-21 were able to induce the formation of ectopic germinal centers and promote the differentiation of naïve B cells within these centers into immunoglobulin G4 (IgG4)-producing plasmablasts. These plasmablasts secrete fibrotic factors like platelet-derived growth factors, which activate fibroblasts and myofibroblasts, leading to uncontrolled fibroblasts.¹⁰⁹ IL-6 and IL-21 promote the expression of amphiregulin in Th17 cells by activating STAT3. STAT3 in turn activates mTOR and mitogen-activated protein (MEK), promotes the proliferation and motility of human intestinal myofibroblasts and the expression of type I collagen. These ultimately contribute to the intestinal fibrosis response.¹¹⁰ IL-17 antibody therapy could significantly reduce TNBS-induced colorectal fibrosis in mice by downregulating the expression of collagen III and several pro-fibrotic cytokines. However, it is important to note that IL-17 antibody treatment alone is not sufficient to completely prevent the progression of intestinal fibrosis, suggesting the involvement of other important factors in the pathogenesis of intestinal fibrosis.¹⁰³ A p40 peptide-based vaccine targeting the IL-12/IL-23 pathway has demonstrated the ability to reduce the percentage of Th1 and Th17 cells in the mesenteric lymph nodes in TNBS-induced chronic colitis. This reduction in Th1 and Th17 cells leads to a decrease in collagen deposition in the colonic tissue, effectively inhibiting intestinal fibrosis.¹¹¹

Factors affecting the pathogenicity of Th17 cells

In general, the ability of Th17 cells to induce EAE after adoptive transfers is used as a criterion for their pathogenicity.¹⁶ Steady-state Th17 cells that undergo the typical metabolism of stationary or memory T cells show limited plasticity and do not contribute to the inflammatory process. These T-cell subsets have distinct expression profiles of cytokines with decreased IL-23R and IL-1R but increased IL-10. Conversely, Th17 cells induced by infection exhibit increased expression of pro-inflammatory cytokines and decreased expression of IL-10. These cells demonstrate high plasticity in the expression of pro-inflammatory cytokines and can be found widely in the periphery.¹⁶ The molecular mediators that regulate these changes are usually induced by the microenvironment and affect the pathogenicity of Th17 cells by regulating cytokines, the transcription factor RORγt, and metabolic patterns.¹⁶

IL-23 is a key determinant of pathogenicity and autoimmunity of Th17 cells. B lymphocyte-induced maturation protein 1 (Blimp-1), an important transcription factor downstream of IL-23, can co-localize with RORγt, STAT3, and histone acetyltransferase p300 in the IL-23R, IL-17A/F, and GM-CSF cytokine loci, increasing their expression and driving the pro-inflammatory function of Th17 cells.¹¹² CD5-like (CD5L), a member of the cysteine-rich clearance receptor superfamily, is involved in the regulation of lipid metabolism and can affect the activity of RORγt by influencing the expression of key cholesterol biosynthetase. In the presence of IL-23, the loss of CD5L allows non-pathogenic Th17 cells to transform into autoimmune-induced pathogenic cells.¹¹³ The canonical Notch signaling mediator for immunoglobulin κJ (RBPJ) is a regulator of the Notch signaling pathway that directly increases IL-23R expression and inhibits IL-10 production, thereby promoting the pathogenicity of Th17 cells.¹¹⁴ Protein C receptor (PROCR) inhibits Th17 differentiation in vitro but it does not globally inhibit the Th17 response. PROCR selectively inhibits pathogenic pro-inflammatory Th17 cells by inhibiting the expression of IL-23R and IL-1R.¹¹⁵

Besides IL-23, many other cytokines can influence the pathogenicity of Th17 cells. TGF-β is necessary for Th17 cells to consistently express IL-17A and IL-17F. However, TGF-β1 can hinder the activation of extracellular regulated protein kinases, which are essential for the development of pathogenic Th17 cells. Consequently, Th17 cells induced by IL-6 and TGF-β1 may not be pathogenic.¹¹⁶ Interestingly, Th17 cells induced by IL-6 and TGF-β3 exhibit high levels of IL-23R expression and demonstrate strong pathogenicity.¹¹⁷ Activin-A, a cytokine from the TGF-β superfamily, is induced during autoimmune neuroinflammation and drives the differentiation of pathogenic Th17 cells.¹¹⁶ TNF-α enhances IL-23-induced IL-17 expression through an IL-1β-dependent mechanism, thereby increasing the pathogenicity of Th17 cells in EAE.¹¹⁸ In a mouse uveitis model, the binding of IL-17A to its receptor led to activation of NF-κB and induction of IL-24, which acted as an autocrine feedback mechanism to inhibit the pathogenicity of Th17 cells.¹¹⁹

In humans, RORγt has been reported to directly inhibit the gene transcription of prostaglandin E receptor (PTGER) 2 that encodes the prostaglandin receptor EP2 in normal Th17 cells, preventing the inducement of pathogenic Th17 cells. Th17 cells from patients with multiple sclerosis exhibit reduced binding of RORγt to the PTGER2 promoter region, resulting in higher levels of EP2, IFN-γ, and GM-CSF.¹²⁰

Serum/glucocorticoid-regulated kinase 1 (SGK1) is a key regulator of sodium transport and is found to be increased in peripheral blood mononuclear cells, particularly Th17 cells, in patients with UC¹²¹. In an in vitro study, Kleinewietfeld et al.¹²² found that an increase in NaCl concentration specifically promoted the transdifferentiation of highly pathogenic Th17 cell types through the p38/MAPK → NFAT5 → SGK1 pathways.¹²² IL-23 activated SGK1 via the mTOR pathway while SGK1, in turn, maintained a feedback loop with IL-23 through phosphorylation of FOXO1.¹²³ RAN-binding protein 1 (RANBP1), a downstream effector of the SGK1 pathway, affects FOXO1 transport from the nucleus to the cytoplasm, thereby facilitating enabling RORγt activation.^124,125 Moreover, excessive NaCl also induced the transdifferentiation of Treg cells into a pro-inflammatory phenotype that expressed IFN-γ, IL-17A, and RORγt, causing them to lose their immunosuppressive effects.¹²⁶

In terms of metabolism, pathogenic Th17 cells not only undergo oxidative phosphorylation typical of inflammatory effector cells but also undergo aerobic glycolysis. The pathogenicity may be related to arginine and downstream polyamine metabolism.^127,128 Blocking glycolysis-related genes phosphoglycerate kinase-1 (PGK1) and aldolase-A (ALDOA) may have therapeutic effects on CD by favoring Th17 cells to acquire regulatory properties and control their pathogenic potential.¹²⁹ The absence of the glycolytic enzyme glucose phosphate isomerase (Gpi1) eliminates pathogenic Th17 cells selectively without affecting steady-state Th17 cells, making it a potentially effective treatment strategy for IBD.¹³⁰

Protective roles of Th17 cells in IBD

Th17 cells maintain intestinal homeostasis

Th17 cells, which can exist in steady-state conditions without causing harm to the intestine, demonstrate a non-pathogenic aspect. In a normal immune state, Th17 cells can be protective. Th17 cells promote the proliferation and maturation of other immune cells and offer resistance against infection by extracellular microorganisms. In addition, they play a role in safeguarding mucosa and epithelial tissues.⁷⁷

Segmented filamentous bacteria (SFB) is a key factor that drives the development of steady-state tissue-resident Th17 cells in the gastrointestinal tract. SFB’s flagellin promotes the expression of IL-17 and IL-22, leading to changes in the intestinal immune microenvironment.¹³¹ In addition, Th17 cells can regulate the abundance of SFB load through the IL-17R signaling pathway, preventing excessive expansion of Th17 cells and the onset of autoimmune inflammation.¹³² SFB is only found in the intestines during the first 3 years of human life and disappears in adults. This suggests that SFB may contribute to the maturation of intestinal immune function and the establishment of the initial intestinal immune barrier by promoting the development of Th17 cells and the expression of mucosal IgA after weaning.^133,134 However, in certain disease models, colonization of SFB could also trigger pathological reactions in peripheral Th17 cells, leading to autoimmune arthritis and EAE. These findings imply a potential association between intestinal Th17 cells and the development of autoimmune diseases in other organs.^135,136

In addition, in intestinal Peyer’s patches, Th17 cells maintain intestinal homeostasis by transitioning to the follicular helper T-cell phenotype, which leads to the activation of B cells at the center of germination. This activation process results in the production of T-cell-dependent host-protective IgA antibodies. It has been observed that mice lacking Th17 cells are unable to generate an antigen-specific IgA response.¹³⁷

Th17 cells exert a protective effect by secreting IL-17A

IL-17A induces the formation of tight connections in human IECs by activating extracellular signal-related MAPK pathways. The expression of claudin-2 in IECs is dependent on MEK activity. In a DSS-induced mouse colitis model, IL-17A might enhance the formation of tight connections between IECs by inducing claudin expression.¹³⁸ Microbiota-driven fibroblast growth factor 2 (FGF2) and IL-17 collaborate to repair intestinal epithelial damage through Act1-mediated direct signal crosstalk.¹³⁹ IL-17A also stimulates mucin secretion by goblet cells and facilitates the transcytosis of IgA by epithelial cells in the human small intestinal organoid model, providing protective effects on the intestine.⁸⁴ In a mouse model with spontaneous production of CD4⁺ T cells reactive to an antigen expressed in the ileum, Th17 cells could promote ileal crypt hyperplasia and ileal reactive Treg accumulation through IL-17A, and self-tolerate antigens expressed in the ileum, thereby maintaining ileal homeostasis and preventing the occurrence of colitis.¹⁴⁰ Maxwell et al.¹⁴¹ found several beneficial roles of IL-17 in the gut in the context of controlling microbial exposure and disease susceptibility. These roles include induction of antimicrobial peptides, recruitment of neutrophils, and maintenance of the epithelial barrier. In their experiment with multidrug resistance-1a-ablated (Abcb1a^−/−) mice infected with Helicobacter bilis, the inhibition of IL-17A or IL-17RA resulted in weakened intestinal epithelial barrier function, leading to increased colitis symptoms and mortality. This was accompanied by an increased proportion of IFN-γ⁺ IL-17A⁺ T helper cells and a decreased proportion of Treg cells. In addition, Zhu et al. also demonstrated that the absence of IL-17A enhanced Helicobacter hepaticus colonization and induced colitis. This effect may be attributed to the impairment of the intestinal epithelium integrity, reduced mucus secretion and colonic mucosal regeneration, and decreased ability to resist microbial infections.¹⁴²

Nishikawa discovered that the intrinsic layer leukocytes in the inflamed colon of IL-17 knockout mice had a lower number of CD11b⁺ Ly6C⁺ MHCII⁺ macrophages. IL-17 can prevent the development of severe colitis by inducing blood monocytes to differentiate into atypical M2-like macrophage subsets in the inflamed colon.¹⁴³ In mice with IL-10-deficient spontaneous colitis, IL-17A inhibits myeloid-derived suppressor cell differentiation and/or proliferation in an inducible nitric oxide synthetase (iNOS)-dependent manner, thereby reducing colon inflammation levels.¹⁴⁴ Furthermore, IL-17A may inhibit the differentiation of Th1 cells by suppressing T-bet and promoting the recruitment of neutrophils to the inflamed regions, thus exerting a protective role in the CD45RB^hi transfer model of colitis.¹⁴⁵

Th17 cells exert a protective effect by secreting IL-22

IL-22 is a member of the IL-10 family and can be produced by innate and adaptive immune cells. It has been shown that IL-22⁺ cells were increased in the inflamed intestinal mucosa of patients with active IBD.¹⁴⁶ Th17 cells express higher levels of IL-22 compared to Th1 or Th2 cells. However, the number of IL-22⁺ IL-17A⁺ T helper cells in the inflamed intestinal mucosal intrinsic layer of IBD did not significantly differ from that of healthy individuals.⁷³ IL-23 enhances the amplification of IL-22-producing cells during Th17 differentiation, and AHR is necessary for IL-22 expression.¹⁴⁷ While TGF-β inhibits the production of IL-22 in a dose-dependent manner, IL-17A can inhibit the expression of IL-22 in Th17 cells partially in vitro and in vivo.¹⁴⁸ The STAT3 signal cascade pathway can also be inter-regulated with IL-22.¹⁴⁹

IL-22 has both pro-inflammatory and protective effects, depending on the inflammatory microenvironment. On the one hand, IL-22 plays a protective role in IBD and serves as the core of the host’s immune barrier against bacterial infection.¹⁵⁰ By activating the JAK-STAT signal pathway, IL-22 not only induces the production of antimicrobial peptides to defend against bacterial pathogens but also promotes the proliferation, differentiation, and migration of IECs while inhibiting their apoptosis. As a result, it enhances intestinal barrier integrity and inherent immunity of the epithelium, contributing to the repair and regeneration of epithelial cells after inflammatory damage.¹⁴⁹ In vitro IL-22 therapy has been shown to promote the expression of tight junction proteins in IECs, such as claudin-1 and zonula occludens-1, which can alleviate damage to these cells.¹⁵¹ AHR is associated with the production of IL-22 and can inhibit mouse colitis by upregulating IL-22. AHR is downregulated in the intestinal mucosa of patients with IBD, causing the intestine to lose the protective effect of IL-22.¹⁵² Both mice and humans have IL-22R1 present on IECs and myofibroblasts. IL-22 gene delivery specifically enhances STAT3 activation within colonic epithelial cells and induces STAT3-mediated expression of mucus-related proteins and the recovery of mucus-producing goblet cells, leading to rapid improvement in local intestinal inflammation in mouse models of UC.¹⁵³ In myofibroblasts of the human colon, IL-22 may also induce the expression of inflammatory cytokines (IL-6, IL-8, IL-11, and leukemia inhibitory factor), chemokines (CCL7, CXCL1, CXCL2, CXCL3, and CXCL6), MMPs by NF-κB-, AP-1-, and MAPK-dependent pathways, playing a role in the pathophysiology of IBD.¹⁴⁶ However, myofibroblasts may be much less reactive to IL-22 than IECs, suggesting that IL-22 has a more protective role in intestinal inflammation.¹⁵² In addition, IL-22 may inhibit the intestinal microbiota by inducing the expression of certain antimicrobial peptides, potentially enhancing the colonization of certain pathogens.^154,155 In the colon of patients with active CD, the IL22 response transcription module and the endoplasmic reticulum (ER) stress response module are enriched. Therefore, there were also studies suggested that IL-22 was a functionally important driver of colonic ER stress in chronic colitis, and triggered ER stress by inducing TNF-α, iNos2, apoptosis-inducing caspase 12, stimulator of interferon genes (STING), Toll-like receptor 4, and MyD88.^156,157

Conclusion

The function of Th17 cells changes dynamically according to the intestinal environment of IBD, which reflects the adaptability of the intestinal immune response. The failure of human anti-IL-17A monoclonal antibody secukinumab in CD therapy indicates a possible protective role of IL-17A. By contrast, blocking cytokines more associated with pathogenic Th17 cells such as IL-12, IL-21, IL-23, and their receptors, or promoting IL-22 expression may have better performance and application prospects in the treatment of IBD, which is worthy of further exploration.^24,141,158 In addition, since inflammation is a process of dynamic equilibrium, we not only need to continue to study more influencing factors and key molecules in the regulatory mechanism of Th17 cell differentiation and function but also need to pay attention to whether these influencing factors will have different effects on inflammation and Th17 cells at different doses, such as whether there will be a shift in pro-inflammatory and anti-inflammatory effects at a certain dose. Moreover, human and mouse Th17 cells are not identical, so it is important to conduct both animal and human studies for translational research. In conclusion, we still have many unknowns to explore in terms of the roles of Th17 cells in IBD.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Ge Wang

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TH17 cell: a double-edged sword in the development of inflammatory bowel disease

Abstract

Keywords

Introduction

Differentiation of Th17 cells

Plasticity of Th17 cells in IBD

Factors affecting the plasticity of Th17 cells

IFN-γ+ IL-17A+ T helper cells

Foxp3+ IL-17A+ T helper cells

IL-17+ CD8+ T cells

Pathogenic roles of Th17 cells in IBD

Migration of Th17 cells in IBD

Th17 cells and the related pathogenic cytokines

Th17 cells promote the recruitment of neutrophils

Th17 cells promote pathological intestinal fibrosis

Factors affecting the pathogenicity of Th17 cells

Protective roles of Th17 cells in IBD

Th17 cells maintain intestinal homeostasis

Th17 cells exert a protective effect by secreting IL-17A

Th17 cells exert a protective effect by secreting IL-22

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References

IFN-γ⁺ IL-17A⁺ T helper cells

Foxp3⁺ IL-17A⁺ T helper cells

IL-17⁺ CD8⁺ T cells