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Psoriasis is a common inflammatory systemic disease characterized by pro-inflammatory macrophages activation (M1 macrophage) infiltrated in the dermal layer. How M1 macrophage contributes to psoriasis remains unknown. In this study, we found that adenosine A2A receptor (A2AR) agonist CGS 21680 HCl alleviated the imiquimod (IMQ) and mouse IL-23 Protein (rmIL-23)-induced psoriasis inflammation through reducing infiltration of M1. Conversely, Adora2a deletion in mice exacerbated psoriasis-like phenotype. Mechanistically, A2AR activation inhibited M1 macrophage activation via the NF-κB-KRT16 pathway to reduce the secretion of CXCL10/11 and inhibit Th1/17 differentiation. Notably, the KRT16 expression was first found in M1 macrophage in our study, not only in keratinocytes (KCs). CXCL10/11 are first identified as primarily derived from macrophages and dendritic cells (DCs) rather than KCs in psoriasis using single cell RNA sequencing (scRNA-Seq). In total, the study emphasizes the importance of M1 as an innate immune cell in pathogenesis of psoriasis.
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Inmunidad Adaptativa , Inmunidad Innata , Activación de Macrófagos , Macrófagos , Psoriasis , Receptor de Adenosina A2A , Animales , Humanos , Ratones , Inmunidad Adaptativa/efectos de los fármacos , Adenosina/análogos & derivados , Agonistas del Receptor de Adenosina A2/farmacología , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/inmunología , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Imiquimod/farmacología , Inmunidad Innata/efectos de los fármacos , Queratinocitos/inmunología , Queratinocitos/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Fenetilaminas/farmacología , Psoriasis/inmunología , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A2A/genéticaRESUMEN
In juvenile idiopathic arthritis (JIA) inflammatory T cells and their produced cytokines are drug targets and play a role in disease pathogenesis. Despite their clinical importance, the sources and types of inflammatory T cells involved remain unclear. T cells respond to polarizing factors to initiate types of immunity to fight infections, which include immunity types 1 (T1), 2 (T2), and 3 (T17). Polarizing factors drive CD4+ T cells towards T helper (Th) cell subtypes and CD8+ T cells towards cytotoxic T cell (Tc) subtypes. T1 and T17 polarization are associated with autoimmunity and production of the cytokines IFNγ and IL-17 respectively. We show that JIA and child healthy control (HC) peripheral blood mononuclear cells are remarkably similar, with the same frequencies of CD4+ and CD8+ naïve and memory T cell subsets, T cell proliferation, and CD4+ and CD8+ T cell subsets upon T1, T2, and T17 polarization. Yet, under T1 polarizing conditions JIA cells produced increased IFNγ and inappropriately produced IL-17. Under T17 polarizing conditions JIA T cells produced increased IL-17. Gene expression of IFNγ, IL-17, Tbet, and RORγT by quantitative PCR and RNA sequencing revealed activation of immune responses and inappropriate activation of IL-17 signaling pathways in JIA polarized T1 cells. The polarized JIA T1 cells were comprised of Th and Tc cells, with Th cells producing IFNγ (Th1), IL-17 (Th17), and both IFNγ-IL-17 (Th1.17) and Tc cells producing IFNγ (Tc1). The JIA polarized CD4+ T1 cells expressed both Tbet and RORγT, with higher expression of the transcription factors associated with higher frequency of IL-17 producing cells. T1 polarized naïve CD4+ cells from JIA also produced more IFNγ and more IL-17 than HC. We show that in JIA T1 polarization inappropriately generates Th1, Th17, and Th1.17 cells. Our data provides a tool for studying the development of heterogeneous inflammatory T cells in JIA under T1 polarizing conditions and for identifying pathogenic immune cells that are important as drug targets and diagnostic markers.
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Artritis Juvenil , Interleucina-17 , Linfocitos T CD8-positivos/metabolismo , Niño , Citocinas , Humanos , Interleucina-17/metabolismo , Leucocitos Mononucleares , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Células TH1RESUMEN
COVID-19 is a respiratory infection similar to viral pneumonia and is caused by SARS-CoV-2. Chloroquine and hydroxychloroquine make up the major part of the treatment regimen for the management of COVID-19 infections, which are also commonly used in treatment of patients with malaria as well as autoimmune diseases like rheumatoid arthritis (RA). In this review, we analyzed the scientific evidences pertaining to any possible association of SARS-CoV-2 infection with RA. We thus believe that people predisposed to RA carry a higher infection risk than the general population both due to the iatrogenic effects of the RA related drug therapy. Thus COVID-19 pandemic may bring a higher risk of health emergency in complex diseases such as RA.
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Enterobacteriaceae are a large family of Gram-negative bacteria that includes both commensals and opportunistic pathogens. The latter can cause severe nosocomial infections, with outbreaks of multi-antibiotics resistant strains, thus being a major public health threat. In this study, we report that Enterobacteriaceae-reactive memory Th cells were highly enriched in a CCR6+ CXCR3+ Th1*/17 cell subset and produced IFN-γ, IL-17A, and IL-22. This T cell subset was severely reduced in septic patients with K. pneumoniae bloodstream infection who also selectively lacked circulating K. pneumonie-reactive T cells. By combining heterologous antigenic stimulation, single cell cloning and TCR Vß sequencing, we demonstrate that a large fraction of memory Th cell clones was broadly cross-reactive to several Enterobacteriaceae species. These cross-reactive Th cell clones were expanded in vivo and a large fraction of them recognized the conserved outer membrane protein A antigen. Interestingly, Enterobacteriaceae broadly cross-reactive T cells were also prominent among in vitro primed naïve T cells. Collectively, these data point to the existence of immunodominant T cell epitopes shared among different Enterobacteriaceae species and targeted by cross-reactive T cells that are readily found in the pre-immune repertoire and are clonally expanded in the memory repertoire.
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Linfocitos T CD4-Positivos/inmunología , Enterobacteriaceae/inmunología , Memoria Inmunológica/inmunología , Células Cultivadas , Reacciones Cruzadas/inmunología , Epítopos de Linfocito T/inmunología , Humanos , Interferón gamma/inmunología , Interleucina-17/inmunología , Interleucinas/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Subgrupos de Linfocitos T/inmunología , Células TH1/inmunología , Células Th17/inmunología , Interleucina-22RESUMEN
Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered to be critical regulators of thymic inflammation in AChR-MG patients. However, Th17 cells are functionally heterogeneous and circulating Th17 subsets are incompletely understood in AChR-MG patients. Here, we studied characteristics of Th17 subsets in peripheral blood from treatment-naïve AChR-MG patients, patients treated with immunosuppressants, as well as healthy controls. We found increased frequencies of circulating Th1-like Th17 (Th1/17) (IFN-γ + IL-17 + CD4 + CD3+) cells, which declined earlier than conventional Th17 (IFN-γ - IL-17 + CD4 + CD3+) cells in patients who respond well to immunosuppression treatment. Additionally, circulating Th1/17 cell frequencies were found to correlate positively with disease severity. Further, compared to conventional Th17 cells, Th1/17 cells showed an elevated expression of IFNG, TBX21, IL23R, CSF2, and a reduced expression of AHR and IL10. Taken together, our results suggest circulating Th1/17 cells may serve as a biomarker of disease severity and provide a strong rationale for early intervention in AChR-MG patients.
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Miastenia Gravis/inmunología , Células TH1/inmunología , Células Th17/inmunología , Adulto , Biomarcadores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores Colinérgicos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: Th1.17 are highly polyfunctional, potentially harmful CD4+ effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in negative regulation mechanisms. We recently demonstrated that the ecto-nucleotidase CD73 delineates a Th1.17-enriched Teff population and acts as an endogenous regulatory mechanism. Because Methotrexate (MTX), used as first line treatment of RA and PsA, increases extracellular concentrations of AMP and immunosuppressive adenosine, we investigated the modulation of CD73 by MTX treatment on Teff in RA/PsA patients. METHODS: In a prospective cohort of 26 RA and 15 PsA patients before or under MTX treatment, we evaluated CD73 expression on blood Teff subsets, their cytokine production and AMPase functions. RESULTS: We showed a decreased CD73 expression on Th1.17 and Th1 in untreated patients compared to healthy donors that was partly restored under MTX. This decrease in untreated patients leads to a halved Ado production by Th1.17 cells. CD73+ Teff remained functional under MTX treatment, but their CD73 re-expression may contribute to control their activation. CONCLUSION: Our study unveils uncovered mode of action of MTX on Teff subsets modulation and in the adenosine-dependent termination of inflammation in RA and PsA.
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We investigated the potency of TAK-828F, a RORγt inverse agonist, in murine experimental autoimmune encephalomyelitis (EAE) model. TAK-828F inhibited the differentiation of Th17 and Th1/17 cells in inguinal lymph node. Increase of these cells in central nervous system (CNS) was also inhibited by TAK-828F. Prophylactic and therapeutic treatments of TAK-828F were efficacious in the model. Plasma concentration of TAK-828F was higher than that in CNS. These results indicate that TAK-828F mainly acts at peripheral and results in the reduction of Th17- and Th1/17-dependent inflammation in CNS. Blocking RORγt may be a promising strategy for treatment of multiple sclerosis.
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Acetatos/farmacología , Encefalomielitis Autoinmune Experimental/inmunología , Naftiridinas/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Animales , Diferenciación Celular/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunologíaRESUMEN
BACKGROUND: Vitiligo is an autoimmune disease with varying pathological features. Activation of the CCL20-CCR6 axis plays an important role in chronic inflammatory diseases. However, whether CCL20-CCR6 and Th1/17 cells are indicative of active vitiligo is unclear. OBJECTIVE: To investigate the potential role of CCL20 and the involvement of Th1/17 and Tc1/17 cells in the mechanism in vitiligo. METHODS: One hundred patients with vitiligo, and 20 healthy controls were included. The serum and blister fluid IL-17, IFN-γ, CCL20, and CXCL10 were studied using enzyme-linked immunosorbent assays. The numbers of Th1/17 cells and Tc1/17 cells in circulation were quantified using flow cytometry. CCR6 mRNA in peripheral blood mononuclear cells (PBMCs) was analyzed by real-time polymerase chain reaction and the protein level was confirmed by western blotting. CCR6 and CCL20 expression in lesions was analyzed by immunohistochemistry. RESULTS: The serum CCL20 level was significantly elevated in patients with vitiligo. The level of serum CCL20 was higher in active than in the stable stage, which correlated positively with the Vitiligo European Task Force spreading score and the Vitiligo Area Scoring Index score. Patients with active vitiligo had elevated numbers of circulating Th1/17 cells and Tc1/17 cells, and upregulated expression of CCR6 in PBMCs and lesions. After effective treatment, the level of CCL20 in sera and blister fluid was significantly decreased, as were the numbers of circulating Th1/17 cells and Tc1/17 cells. CONCLUSION: CCL20 might be a vital biomarker of active vitiligo, and circulating Th1/17 and Tc1/17 cells are involved in the pathogenesis of vitiligo.
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Quimiocina CCL20/sangre , Células TH1 , Células Th17 , Vitíligo/diagnóstico , Adulto , Biomarcadores/sangre , Biomarcadores/metabolismo , Quimiocina CCL20/metabolismo , Estudios de Cohortes , Femenino , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Receptores CCR6/metabolismo , Índice de Severidad de la Enfermedad , Piel/patología , Linfocitos T Citotóxicos , Vitíligo/sangre , Vitíligo/patología , Adulto JovenRESUMEN
OBJECTIVE AND DESIGN: Protease activity of MALT lymphoma-translocation protein 1 (Malt1) plays an important role in the development of colitis, but the detailed mechanism has not been fully elucidated. METHOD: Effects of Malt1 protease on the activation of T cells and the development of experimental colitis was investigated using Malt1 protease-deficient (PD) mouse. RESULTS: IL-2 production from CD4+ T cells of Malt1 PD mice was decreased compared with that of wild-type (WT) mice. Intraperitoneal injection of anti-CD3 antibody into Malt1 PD mouse induced less productions of IL-17 in the plasma, as well as the colonic gene expression of IL-17A, compared with WT mice, whereas IFN-γ production was not impaired. In naïve T-cell transfer colitis model, Malt1 PD T cells induced less disease severity than WT T cells. Then, reduction in the populations of Th17 and Th1/17 cells was observed in the mesenteric lymph nodes of the recipient mice transferred with Malt1 PD T cells, whereas those of Th1 cells were not impaired. IL-17A expression in the colon was also decreased in the mouse receiving Malt1 PD T cells. CONCLUSIONS: Inactivation of Malt1 protease activity abrogates Th17 and Th1/17 cell activation, resulting in the amelioration of experimental colitis.
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Linfocitos T CD4-Positivos/inmunología , Citocinas/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD4-Positivos/trasplante , Colitis/inmunología , Colon/inmunología , Femenino , Ganglios Linfáticos/inmunología , Ratones Endogámicos BALB C , Ratones SCIDRESUMEN
IL-17-producing Th17 cells and IFN-γ and IL-17 double-producing Th1/17 cells have been identified as the pathogenic cells in inflammatory bowel disease (IBD). Retinoic acid-related orphan receptor γt (RORγt) is a master regulator for the differentiation and activation of Th17 and Th1/17 cells. We discovered a novel orally available TAK-828F, a strong and selective RORγt inverse agonist. To assess the potential of RORγt blockade in the therapy for IBD, the efficacy of TAK-828F in activated T cell transfer mouse colitis model was investigated. This model was highly sensitive to the prophylactic treatment of anti-TNF-α monoclonal antibody but partially susceptible to sulfasalazine, tacrolimus, and prednisolone. Oral administration of TAK-828F, at doses of 1 and 3 mg/kg, b.i.d, strongly protected the progression of colitis. TAK-828F decreased the population of Th17 and Th1/17 cells in a dose-dependent manner in the mesenteric lymph node. Moreover, expression of mRNA that are characteristic of the Th17 signature, such as IL-17A and IL-17F in the colon, were inhibited by TAK-828F, while the expression of IL-10, an anti-inflammatory cytokine, was increased. In the therapeutic treatment, TAK-828F lessened disease severity compared to the vehicle control mice. Interestingly, gene expression of zonula occludens-1 (ZO-1) and mucin 2 (Muc2), which play an important role in barrier function of the intestinal mucosa, was recovered by TAK-828F. These results indicate that blocking RORγt has promising pharmacological profile in the colitis model. RORγt blockade may provide a novel therapeutic paradigm for treatment of IBD with unique mechanism by which improves imbalance of the immune system.
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Acetatos/farmacología , Colitis/tratamiento farmacológico , Agonismo Inverso de Drogas , Naftiridinas/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Mucosa Intestinal/metabolismo , Ganglios Linfáticos/citología , Ratones , Células Th17/citología , Células Th17/efectos de los fármacosRESUMEN
MDR1 is an ATP-dependent transmembrane transporter primarily studied for its role in the detoxification of tissues and for its implication in resistance of tumor cells to chemotherapy treatment. Several studies also report on its expression on immune cells where it plays a protective role from xenobiotics and toxins. This review provides an overview of what is known on MDR1 expression in immune cells in human, and its implications in different pathologies and their treatment options.
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Retinoic acid-related orphan receptor γt (RORγt) is a key master regulator of the differentiation and activation of IL-17 producing CD4+ Th17, CD8+ Tc17 and IL-17/IFN-γ co-producing cells (Th1/17 cells). These cells play critical roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease and multiple sclerosis. Thus, RORγt is an attractive target for the treatment of these diseases. We discovered TAK-828F, an orally available potent and selective RORγt inverse agonist. The inhibitory effect on the activation and differentiation of Th17 cells by TAK-828F was evaluated in mouse and human primary cells. TAK-828F inhibited IL-17 production from mouse splenocytes and human peripheral blood mononuclear cells dose-dependently at concentrations of 0.01-10⯵M without affecting the production of IFN-γ. Additionally, TAK-828F strongly inhibited Th17, Tc17 and Th1/17 cells' differentiation from naive T cells and memory CD4+ T cells at 100â¯nM without affecting Th1 cells' differentiation. In addition, TAK-828F improved Th17/Treg cells' population ratio by inhibiting Th17 cells' differentiation and up-regulating Treg cells. Furthermore, TAK-828F, at 100â¯nM, reduced the production of Th17-related cytokines (IL-17, IL-17F and IL-22) without affecting IFN-γ production in whole blood. These results demonstrate that TAK-828F has the potent and selective inhibitory activity against RORγt both in mouse and human cells. Additionally, oral administration of TAK-828F showed promising efficacy in naive T cell transfer mouse colitis model. TAK-828F may provide a novel therapeutic option to treat immune diseases by inhibiting Th17 and Th1/17 cells' differentiation and improving imbalance between Th17 and Treg cells.
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Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/fisiología , Administración Oral , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interleucina-17/antagonistas & inhibidores , Interleucina-17/fisiología , Receptores de Lipopolisacáridos/antagonistas & inhibidores , Receptores de Lipopolisacáridos/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Células Th17/efectos de los fármacos , Células Th17/fisiologíaRESUMEN
Multiple sclerosis (MS) and the corresponding animal model, experimental autoimmune encephalomyelitis (EAE), are chronic neuroinflammatory autoimmune diseases. Increased activation of CD4+T cells, especially the Th1 and Th17 subsets, is thought to play a causal role in this disease. IFN-ß is widely used in the treatment of MS and is found to decrease IL-17 and OPN production in MS patients and EAE mice. However, a definitive molecular mechanism has not yet been fully elucidated. In this study, we investigated the immunomodulatory effect of IFN-ß on the EAE model. We observed disease progression and determined the percentage of Th1/Th17 cells in the peripheral immune organs, brain, and spinal cord of mice. Furthermore, the levels of related cytokines and transcription factors were measured in splenocytes, and the effects of IFN-ß on Th17 differentiation were assessed in vitro. Compared to the control group, IFN-ß treatment significantly reduced the incidence of EAE and the associated pathological damage. Th1 and Th17 cells in IFN-ß-treated mice were significantly reduced, and the levels of cytokines, such as IFN-γ, IL-17, and OPN, were significantly decreased in splenocyte supernatants as well as the levels of corresponding transcription factors. IFN-ß inhibited downstream inflammatory cytokines through the inhibition of PI3K/AKT/NF-κB axis and p38, JNK-MAPK, as well as the regulation of mTOR complexes. Moreover, IFN-ß inhibited Th17 differentiation and neutralizing OPN antibodies offset the inhibitory effect of IFN-ß on Th17 cells. Meanwhile, IFN-ß influenced the acetylation of the Il17a and Opn gene promoters. The findings described herein provide novel evidence for the role of IFN-ß in Th17 differentiation partly through the inhibition of OPN.
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Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Interferón beta/fisiología , Osteopontina/fisiología , Células Th17/efectos de los fármacos , Animales , Células Cultivadas , Citocinas/biosíntesis , Citocinas/genética , Regulación hacia Abajo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Inmunosupresores/farmacología , Interferón beta/farmacología , Interferón beta/uso terapéutico , Linfopoyesis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/inmunología , Glicoproteína Mielina-Oligodendrócito/toxicidad , Osteopontina/antagonistas & inhibidores , Osteopontina/biosíntesis , Osteopontina/genética , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/toxicidad , Regiones Promotoras Genéticas/efectos de los fármacos , Distribución Aleatoria , Organismos Libres de Patógenos Específicos , Médula Espinal/química , Médula Espinal/patología , Especificidad del Receptor de Antígeno de Linfocitos T , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/inmunología , Células Th17/metabolismo , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
IL-27 is a heterodimeric cytokine that is composed of two subunits, i.e., EBV-induced gene 3 and IL-27p28 (also known as IL-30). Although the role of endogenous IL-27 in the pathogenesis of autoimmune colitis, an experimental model of human inflammatory bowel disease, remains controversial, IL-27 local delivery has been shown to inhibit autoimmune colitis. IL-30 has been shown to inhibit Th1 and Th17 responses and is considered a potential therapeutic for certain autoimmune diseases. In this study, we have compared the therapeutic efficacy of adeno-associated viral vector-delivered IL-27 and IL-30 in a murine model of autoimmune colitis. We found that 1 single administration of adeno-associated viral vector-delivered IL-27, but not adeno-associated viral vector-delivered IL-30, nearly completely inhibited autoimmune colitis. Adeno-associated viral vector-delivered IL-27 administration inhibited Th17 responses and induced T cell expression of IL-10, programmed death ligand 1, and stem cell antigen 1. Intriguingly, adeno-associated viral vector-delivered IL-27 treatment enhanced Th1 responses and inhibited regulatory T cell responses. Experiments involving the adoptive transfer of IL-10-deficient T cells revealed that adeno-associated viral vector-delivered IL-27-induced IL-10 production was insufficient to mediate inhibition of autoimmune colitis, whereas anti-programmed death 1 antibody treatment resulted in the breaking of adeno-associated viral vector-delivered IL-27-induced T cell tolerance. Thus, systemic delivery of IL-27 inhibits Th17 responses and induces multiple inhibitory pathways, including programmed death ligand 1 in T cells, and adeno-associated viral vector-delivered IL-27, but not IL-30, may have a therapeutic potential for the treatment of human inflammatory bowel disease.