Human Th17 Cells Research Articles

The Purinergic Receptor P2X4 Promotes Th17 Activation and the Development of Arthritis.

Purinergic signaling plays a major role in T cell activation leading to IL-2 production and proliferation. However, it is unclear whether purinergic signaling contributes to the differentiation and activation of effector T cells. In this study, we found that the purinergic receptor P2X4 was associated with human Th17 cells but not with Th1 cells. Inhibition of P2X4 receptor with the specific antagonist 5-BDBD and small interfering RNA inhibited the development of Th17 cells and the production of IL-17 by effector Th17 cells stimulated via the CD3/CD28 pathway. Our results showed that P2X4 was required for the expression of retinoic acid-related orphan receptor C, which is the master regulator of Th17 cells. In contrast, inhibition of P2X4 receptor had no effect on Th1 cells and on the production of IFN-γ and it did not affect the expression of the transcription factor T-bet (T-box transcription factor). Furthermore, inhibition of P2X4 receptor reduced the production of IL-17 but not of IFN-γ by effector/memory CD4+ T cells isolated from patients with rheumatoid arthritis. In contrast to P2X4, inhibition of P2X7 and P2Y11 receptors had no effects on Th17 and Th1 cell activation. Finally, treatment with the P2X4 receptor antagonist 5-BDBD reduced the severity of collagen-induced arthritis in mice by inhibiting Th17 cell expansion and activation. Our findings provide novel insights into the role of purinergic signaling in T cell activation and identify a critical role for the purinergic receptor P2X4 in Th17 activation and in autoimmune arthritis.

IL-23/Th17 Axis: A Potential Therapeutic Target of Psoriasis.

Psoriasis is an immune-mediated skin disease that leads to the initiation of abnormal production of inflammatory mediators and keratinocytes hyper-proliferation. Th-1 cell expressing cytokines such as IL-1β and TNF-α have been the important hallmarks in the management of psoriasis. However, investigations carried out in the previous few years underline the involvement of another subset of T helper cells, i.e. Th-17 in psoriasis exacerbation, and hence have become the point of focus now. The immunopathogenesis of Th-17 is the result of the IL-23/Th-17 axis. It involves the release of IL-17 and IL-22 in response to the activated NF-kβ dependent activation of IL-23. The function of human Th-17 cells, as well as the crucial role of IL-23/Th-17 axis in the exacerbation of psoriasis and treatment, have been well explored. Therefore, considering IL-23/Th17 axis as a pertinent therapeutic target in immune driven disorders, extensive investigations are now highlighting the utility of biopharmaceuticals and/or biological agents acting on these targets. Here, we review the IL-23/Th-17 axis based therapeutic targets, different types of active moieties based on their source of availability and most useful USFDA approved Mabs targeting the IL-23/Th17 axis in psoriasis for a better understanding of the future possibilities in this area.

P706 A distinct subset of tissue-resident Th17 cells expands in the inflamed intestines of Crohn’s Disease patients and responds to colitogenic bacteria

Abstract Background Inflammatory bowel diseases (IBDs) are characterized by excessive inflammatory T-cell responses to intestinal microbes. Th17-derived Th1 cells (“Th1/17”) are pathogenic in mice, and might also drive inflammation in IBDs.Here, we characterized the role of a novel subset of human intestinal-resident Th17 cells, which produced very high levels of IL-17, together with IFN-γ, in intestinal inflammation in Crohn’s Disease. Methods CD4+T-cell subsets from IBD patients and controls were analysed by RNA sequencing and flow cytometry. They were monitored pre/post-therapies in different tissues, and analysed for antigen specificities. Results CCR6+CCR5+CXCR3-T-helper cells co-expressed RORC and T-bet, and co-produced IL-17 and IFN-γ. These CCR5+Th17-cells were associated with intestinal inflammation in Crohn’s Disease (CD), but not in ulcerative colitis, and contracted upon Infliximab-induced mucosal healing. Conversely, CXCR3+CCR6+Th1/17 cells, which also co-produced IL-17 and IFN-γ, were unaltered. Intestinal CCR5+Th17-cells had up-regulated genes of pro-inflammatory Th17-effector cells, and down-regulated genes involved in recirculation. Consistently, CCR5+Th17-cells were rare in peripheral blood and lymph nodes, displayed a tissue-resident phenotype in the gut and were enriched in the intra-epithelial compartment of CD patients. Conversely, CCR5-Th17-cells were abundant in the circulation, had an increased gut-homing potential in IBDs, and decreased post-Vedolizumab treatment in the intestine. Moreover, they up-regulated CCR5 with IL-23, which was abundant in the guts of CD patients. Importantly, intestinal CCR5+Th17 cells were selectively activated by adherent-invasive Escherichia coli (AIEC), but not by a commensal/probiotic strain. Th1/17-cells responded instead to Cytomegalovirus. Notably, AIEC induced also IL-23 and the CCR5 ligand RANTES from dendritic cells (DCs). Conclusion We identified a gut-resident Th17-cell subset that was activated by CD-associated bacteria, suggesting a key role in pathogenesis. They could differentiate from conventional, circulating Th17-cells that are recruited to the gut and activated by AIEC-infected DCs. Conversely, intestinal Th1/17-cells may protect CD patients from CMV-induced colitis.

Genome-wide DNA methylome and transcriptome changes induced by inorganic nanoparticles in human kidney cells after chronic exposure

The unique physicochemical properties make inorganic nanoparticles (INPs) an exciting tool in diagnosis and disease management. However, as INPs are relatively difficult to fully degrade and excrete, their unintended accumulation in the tissue might result in adverse health effects. Herein, we provide a methylome–transcriptome framework for chronic effects of INPs, commonly used in biomedical applications, in human kidney TH-1 cells. Renal clearance is one of the most important routes of nanoparticle excretion; therefore, a detailed evaluation of nanoparticle-mediated nephrotoxicity is an important task. Integrated analysis of methylome and transcriptome changes induced by INPs (PEG-AuNPs, Fe3O4NPs, SiO2NPs, and TiO2NPs) revealed significantly deregulated genes with functional classification in immune response, DNA damage, and cancer-related pathways. Although most deregulated genes were unique to individual INPs, a relatively high proportion of them encoded the transcription factors. Interestingly, FOS hypermethylation inversely correlating with gene expression was associated with all INPs exposures. Our study emphasizes the need for a more comprehensive investigation of INPs’ biological safety, especially after chronic exposure.Graphical abstract

CD44 v5 domain inhibition represses the polarization of Th2 cells by interfering with the IL-4/IL-4R signaling pathway.

The balance between T helper type 1 (Th1) and T helper type 2 (Th2) cells is critical for both innate and acquired immune reactions. However, the precise mechanisms of T helper-cell differentiation remain unclear. As an important T-cell activation molecule, CD44 participates in the differentiation of Th1 and Th2 cells. We demonstrated that CD44 variant exon v5 (CD44 v5) is highly expressed by induced human Th2 cells. To investigate the role of the CD44 v5 domain in Th2 cell differentiation, we treated human CD4+ T cells with anti-CD44v5 antibody and observed that the levels of phosphorylated STAT6 and GATA3 and the secretion of interleukin-4 (IL-4) were significantly decreased after the treatment. We also further found that the inhibition of Th2 differentiation was caused by the degradation of the alpha chain of IL-4 receptor (IL-4Rα), the CD44 v5 domain colocalized with IL-4Rα on cell surface and the degradation of IL-4Rα increased after CD44 v5 domain blocking or ablating. Our results indicated that CD44v5 antibody treatment interrupted the interaction between CD44 v5 domain and IL-4Rα, but the CD44 v5 domain blockage would not spoil the colocalization between IL-4R expression and T-cell receptor and the immunological synapse formation; similar results were also found in CD44v5-deficient CD4+ T cells. In conclusion, we revealed the function of the CD44 v5 domain in Th2 cell differentiation; blocking or ablating the CD44 v5 domain could accelerate IL-4Rα degradation and then induce the Th2 cell inhibition.

Cav1.4 calcium channels control cytokine production by human peripheral TH17 cells and psoriatic skin-infiltrating T cells

Type-17 inflammation characterizes psoriasis, a chronic skin disease. Because several inflammatory cytokines contribute to psoriasis pathogenesis, inhibiting the simultaneous production of these cytokines in TH17 cells may be beneficial in psoriasis. We found that Cav1.4, encoded by CACNA1F, was the only Cav1 calcium channel expressed in TH17 cells. We sought to investigate the role of Cav1.4 expression in early TH17-activation events and effector functions, as well as its association with TH17 signature genes in lesional psoriatic (LP) skins. Transcriptional gene signatures associated with CACNA1F expression were examined in LP skins by RT-PCR and in situ hybridization. Cav1 inhibitor and/or shRNA lentivectors were used to assess the contribution of Cav1.4 in TH17 activation and effector functions in a 3-dimensional skin reconstruction model. CACNA1F expression correlated with inflammatory cytokine expression that characterizes LP skins and was preferentially associated with RORC expression in CD4+ and CD4- cells from LP biopsies. Nicardipine, a Cav1 channel antagonist, markedly reduced inflammatory cytokine production by TH17 cells from blood or LP skin. This was associated with decreased TCR-induced early calcium events at cell membrane and proximal signaling events. The knockdown of Cav1.4 in TH17 cells impaired cytokine production. Finally, Cav1 inhibition reduced the expression of the keratinocyte genes characteristic of TH17-mediated psoriasis inflammation in human skin equivalents. Cav1.4 channels promote TH17-cell functions both at the periphery and in inflammatory psoriatic skin.

014 C1ORF162 is specifically expressed by pathogenic Th2 cells in atopic dermatitis

Pathogenic Th2 cells are a recently described subpopulation of allergen-specific Th2 cells that are crucial mediators of type 2 immune diseases such as asthma and allergic dermatitis. Understanding the unique biology of pathogenic Th2 cells holds the promise of identifying specific and novel therapeutic targets. The gene chromosome 1 open reading frame 162 (C1ORF162) has been repeatedly identified to be specifically expressed by pathogenic Th2 cells and its expression correlates with disease severity in atopic dermatitis. Yet, its function is completely unknown. Here, we characterized the cellular expression of C1ORF162 at the mRNA and protein level in primary human T cells. RNA sequencing and qPCR analysis confirmed that both in-vivo- and in-vitro- primed Th2 express higher levels of C1ORF162 than Th1 and Th17 cells. In addition, C1ORF162 expression in Th2 cells correlated with the expression of cytokines that are specifically expressed by pathogenic Th2 cells, such as IL-9 and IL-5. These findings were confirmed at the protein level by Western Blot and FACS analysis. Initial protein localization experiments and functional analyses suggest that C1ORF162 is a perinuclear protein that is rapidly downregulated by IL-2 signaling. Finally, C1ORF162 was found to be expressed by T cells infiltrating lesional skin of atopic dermatitis. In conclusion, C1ORF162 is consistently expressed in pathogenic Th2 cells and associated with disease severity in atopic dermatitis. Future experiments aim to further define the identity and function of C1ORF162 in human Th2 cells. Based on the close association of C1ORF162 with pathogenic Th2 cells, these studies may have therapeutic implications for type 2-driven disease in the skin and beyond.

186 TH9 cells depend on cystine uptake and PPAR-γ signaling to prevent unchecked lipid ROS and cell death

TH9 cells, also known as pathogenic TH2 cells, are a subset of proinflammatory effector TH cells characterized by high levels of IL-9 expression. They share many properties with conventional TH2 cells but are distinguished by their expression of the transcription factor PPAR-γ, on which they depend for full effector function. PPAR-γ is best known for its role in controlling lipid and glucose metabolism but is increasingly implicated in type 2 inflammation. However, the role of PPAR-γ in TH9 cells remains unclear. Transcriptional profiling of human TH9 cells in presence or absence of the PPAR-γ inhibitor, GW9662, showed strong upregulation of genes involved in cystine transport and redox control of lipid peroxidation. One of the top upregulated genes was SLC7A11, which encodes a cystine/glutamate transporter. Interestingly, we found that the chemical inhibition of SLC7A11 by erastin and cystine starvation in cystine free medium leads to an increase in lipid ROS levels and cell death in TH9 cells but not in conventional TH2 cells. Moreover, PPAR-γ inhibition promotes a further increase in lipid ROS and cell death upon erastin treatment only in TH9 cells, and this effect was not associated with augmented cellular ROS or mitochondrial ROS. Importantly, the anti-oxidant N-acetylcysteine completely rescued the effect of erastin, alone or in combination with GW9662. Erastin and/or GW9662 were also able to selectively deplete the CCR8+CRTh2+ effector memory T cells isolated from allergic contact dermatitis skin biopsies, which share phenotypic and functional features with TH9 cells. These preliminary data suggest that PPAR-y plays a role in protecting pathogenic TH2 cells from unchecked lipid ROS and consecutive cell death. Our findings open up new therapeutic avenues to selectively target pathogenic TH2 cells in the treatment of allergic diseases by leveraging their particular dependency on cystine to prevent cell death from unchecked lipid ROS.

Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells.

Dysregulated function of Th17 cells has implications in immunodeficiencies and autoimmune disorders. Th17 cell differentiation is orchestrated by a complex network of transcription factors, including several members of the activator protein (AP-1) family. Among the latter, FOSL1 and FOSL2 modulate the effector functions of Th17 cells. However, the molecular mechanisms underlying these effects are unclear, owing to the poorly characterized protein interaction networks of FOSL factors. Here, we establish the first interactomes of FOSL1 and FOSL2 in human Th17 cells, using affinity purification–mass spectrometry analysis. In addition to the known JUN proteins, we identified several novel binding partners of FOSL1 and FOSL2. Gene ontology analysis found a significant fraction of these interactors to be associated with RNA-binding activity, which suggests new mechanistic links. Intriguingly, 29 proteins were found to share interactions with FOSL1 and FOSL2, and these included key regulators of Th17 fate. We further validated the binding partners identified in this study by using parallel reaction monitoring targeted mass spectrometry and other methods. Our study provides key insights into the interaction-based signaling mechanisms of FOSL proteins that potentially govern Th17 cell differentiation and associated pathologies.

STAT5 Represses a STAT3-Independent Th17-like Program during Th9 Cell Differentiation.

IL-9-producing Th cells, termed Th9 cells, contribute to immunity against parasites and cancers but have detrimental roles in allergic disease and colitis. Th9 cells differentiate in response to IL-4 and TGF-β, but these signals are insufficient to drive Th9 differentiation in the absence of IL-2. IL-2-induced STAT5 activation is required for chromatin accessibility within Il9 enhancer and promoter regions and directly transactivates the Il9 locus. STAT5 also suppresses gene expression during Th9 cell development, but these roles are less well defined. In this study, we demonstrate that human allergy-associated Th9 cells exhibited a signature of STAT5-mediated gene repression that is associated with the silencing of a Th17-like transcriptional signature. In murine Th9 cell differentiation, blockade of IL-2/STAT5 signaling induced the expression of IL-17 and the Th17-associated transcription factor Rorγt. However, IL-2-deprived Th9 cells did not exhibit a significant Th17- or STAT3-associated transcriptional signature. Consistent with these observations, differentiation of IL-17-producing cells under these conditions was STAT3-independent but did require Rorγt and BATF. Furthermore, ectopic expression of Rorγt and BATF partially rescued IL-17 production in STAT3-deficient Th17 cells, highlighting the importance of these factors in this process. Although STAT3 was not required for the differentiation of IL-17-producing cells under IL-2-deprived Th9 conditions, their prolonged survival was STAT3-dependent, potentially explaining why STAT3-independent IL-17 production is not commonly observed in vivo. Together, our data suggest that IL-2/STAT5 signaling plays an important role in controlling the balance of a Th9 versus a Th17-like differentiation program in vitro and in allergic disease.

AZD0284, a Potent, Selective, and Orally Bioavailable Inverse Agonist of Retinoic Acid Receptor-Related Orphan Receptor C2.

Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist 2. Extensive structure-activity relationship (SAR) studies resulted in AZD0284 (20), which combined potent inhibition of IL-17A secretion from primary human TH17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical in vivo studies, compound 20 reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, 20 was progressed to phase 1 clinical studies.

Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation

T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes, and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate, which induced cell stress and changes in biosynthesis of cholesterol and lipids, as revealed by single-cell RNA-sequencing analysis. Finally, exposure to glutamate decreased myelination, whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities in MS.

Neonatal T Helper 17 Responses Are Skewed Towards an Immunoregulatory Interleukin-22 Phenotype.

Newborns are frequently affected by mucocutaneous candidiasis. Th17 cells essentially limit mucosal invasion by commensal Candida spp. Here, we sought to understand the molecular basis for the developmental lack of Th17 cell responses in circulating blood neonatal T cells. Naive cord blood CD4 T cells stimulated in Th17-differentiating conditions inherently produced high levels of the interleukin-22 immunoregulatory cytokine, particularly in the presence of neonatal antigen-presenting cells. A genome-wide transcriptome analysis comparing neonatal and adult naïve CD4 T cells ex vivo revealed major developmental differences in gene networks regulating Small Drosophila Mothers Against Decapentaplegic (SMAD) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. These changes were functionally validated by experiments showing that the requirement for TGF-β in human Th17 cell differentiation is age-dependent. Moreover, STAT3 activity was profoundly diminished while overexpression of the STAT3 gene restored Th17 cell differentiation capacity in neonatal T cells. These data reveal that Th17 cell responses are developmentally regulated at the gene expression level in human neonates. These developmental changes may protect newborns against pathological Th17 cell responses, at the same time increasing their susceptibility to mucocutaneous candidiasis.

Sodium chloride generates anti-inflammatory Th17 cell responses but amplifies Th17 cell pathogenicity in pro-inflammatory cytokine microenvironments

Abstract Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. We here demonstrate that together with amplification of human Th17 cell signature properties, NaCl gave rise to a stable anti-inflammatory Th17 cell fate that we found to be restricted to distinct pathogen specificities. The p38/MAPK pathway involving NFAT5 and SGK1regulated FoxP3 and IL-17 expression in high NaCl conditions. The NaCl induced acquisition of an anti-inflammatory Th17 cell fate was confirmed in vivo in the mouse model of experimental autoimmune encephalomyelitis (EAE), which demonstrated strongly reduced disease symptoms upon transfer of NaCl-treated encephalitogenic Th17 cells. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-b low cytokine microenvironment. This revealed a context dependent dichotomous role for NaCl in shaping the pathogenicity of Th17 cells. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in collaboration with cytokine blocking drugs.

Systems analysis of human T helper17 cell differentiation uncovers distinct time-regulated transcriptional modules

SummaryT helper (Th) 17 cells protect from infections and are pathogenic in autoimmunity. While human Th17 cell differentiation has been defined, the global and stepwise transcriptional changes accompanying this process remain uncharacterized. Herein, by performing transcriptome analysis of human Th17 cells, we uncovered three time-regulated modules: early, involving exclusively “signaling pathways” genes; late, characterized by response to infections; and persistent, involving effector immune functions. To assign them an inflammatory or regulatory potential, we compared Th17 cells differentiated in presence or absence of interleukin (IL)-1β, respectively. Most inflammatory genes belong to the persistent module, whereas regulatory genes are lately or persistently induced. Among inflammatory genes, we identified the effector molecules IL17A, IL17F, IL26, IL6, interferon (IFN)G, IFNK, LTA, IL1A, platelet-derived growth factor (PDGF) A and the transcriptional regulators homeodomain-only protein homeobox (HOPX) and sex-determining-region-Y-box (SOX)2, whose expression was independently validated. This study provides an integrative representation of the stepwise human Th17 differentiation program and offers new perspectives toward therapeutic targeting of Th17-related autoimmune diseases.

Decrease of IL-5 Production by Naive T Cells Cocultured with IL-18-Producing BCG-Pulsed Dendritic Cells from Patients Allergic to House Dust Mite.

The only currently available anti-tuberculosis vaccine, Bacillus Calmette–Guérin (BCG), has been reported to also protect against unrelated diseases, including inflammatory diseases such as allergic asthma. Recombinant BCG strains that produce IL-18 have been shown to enhance Th1 responses over non-recombinant BCG and to reduce IL-5 production and bronchoalveolar eosinophilia in mice. However, their ability to decrease the immune polarization of human Th2 cells is not known. Here, we show that BCG and recombinant BCG producing human IL-18 (rBCG-hIL-18) induced the maturation of Der p 1-stimulated monocyte-derived dendritic cells (MD-DCs) from healthy controls and from patients allergic to house dust mites. After incubation with mycobacteria and Der p 1, MD-DCs produced significantly more IL-23 and IP-10 but had no effect on IL-12p70 or IL-10 production compared to Der p 1-pulsed MD-DCs in the absence of mycobacteria. In the presence of Der p 1, BCG- and rBCG-hIL-18-pulsed MD-DCs cocultured with naive, but not with memory T cells from allergic patients, resulted in a decrease in IL-5 production compared to non-pulsed MD-DCs cultured in the presence of Der p 1. BCG, and especially rBCG-hIL-18, may thus be potential therapeutic tools to reduce exacerbated Th2 responses in patients with allergic asthma.

The gut microbiota is a transmissible determinant of skeletal maturation.

Genetic factors account for the majority of the variance of human bone mass, but the contribution of non-genetic factors remains largely unknown. By utilizing maternal/offspring transmission, cohabitation, or fecal material transplantation (FMT) studies, we investigated the influence of the gut microbiome on skeletal maturation. We show that the gut microbiome is a communicable regulator of bone structure and turnover in mice. In addition, we found that the acquisition of a specific bacterial strain, segmented filamentous bacteria (SFB), a gut microbe that induces intestinal Th17 cell expansion, was sufficient to negatively impact skeletal maturation. These findings have significant translational implications, as the identification of methods or timing of microbiome transfer may lead to the development of bacteriotherapeutic interventions to optimize skeletal maturation in humans. Moreover, the transfer of SFB-like microbes capable of triggering the expansion of human Th17 cells during therapeutic FMT procedures could lead to significant bone loss in fecal material recipients.

Genetic and pharmacological inhibition of the nuclear receptor ROR\u03b1 regulates TH17 driven inflammatory disorders

Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered functionally redundant to RORγt; therefore, the function and therapeutic value of RORα in TH17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for TH17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming TH17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.

Cover

The cover image is based on the Original Article Upregulation of miR-9 and miR-193b over human Th17 cell differentiation by Fahimeh Shirani et al., https://doi.org/10.1002/mgg3.1538

Cytokine-regulated Th17 plasticity in human health and diseases.

Upon activation, naïve CD4+ T helper (Th) cells differentiate into distinct Th effector cell lineages depending on the local cytokine environment. However, these polarized Th cells can also adapt their function and phenotype depending on the changing cytokine environment, demonstrating functional plasticity. Here, Th17 cells, which play a critical role in host protection from extracellular pathogens and in autoimmune disorders, are of particular interest. While being able to shift phenotype within their lineage, Th17 cells can also acquire characteristics of Th1, Th2, T follicular helper (Tfh) or regulatory T cells. Th17 cell identity is determined by a spectrum of extracellular signals, including cytokines, which are critical orchestrators of cellular immune responses. Cytokine induces changes in epigenetic, transcriptional, translational and metabolomic parameters. How these signals are integrated to determine Th17 plasticity is not well defined, yet this is a crucial point of investigation as it represents a potential target to treat autoimmune and inflammatory diseases. The goal of this review was to discuss how cytokines regulate intracellular networks, focusing on the regulation of lineage-specific transcription factors, chromatin remodelling and metabolism, to control human Th17 cell plasticity. We discuss the importance of Th17 plasticity in autoimmunity and cancer and present current strategies and challenges in targeting pathogenic Th17 cells with cytokine-based approaches, considering human genetic variants associated with altered Th17 differentiation. Finally, we discuss how modulating Th17 plasticity rather than targeting the Th17 lineage as a whole might preserve its essential immune function while purging its adverse effects.