CD73 is a phenotypic marker of effector memory Th17 cells in inflammatory bowel disease (original) (raw)
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F1000 - Post-publication peer review of the biomedical literature, 2011
BACKGROUND & AIMS-Interleukin (IL)-17-producing CD4 + helper T cells (Th17) mediate mucosal immunity and are involved in the pathogenesis of inflammatory bowel disease (IBD). They are believed to arise from the same precursor population as regulatory T (Treg) cells, but little is known about how these T-cell subsets interact under chronic inflammatory conditions. We studied Th17 cells and Treg cells isolated from intestinal lamina propria of patients with inflammatory bowel disease (IBD) to investigate their role in pathogenesis. METHODS-FoxP3 expression (a marker of Treg cells) and IL-17 production were assessed in CD4 + lamina propria lymphocytes (LPLs) isolated from IBD patients and healthy subjects. IL17 + FoxP3 + and IL-17 + CD4 + T-cell clones were generated by limiting dilution. An in vitro suppression assay was performed to assess the functional capacity of derived T-cell clones. RESULTS-IL17 + FoxP3 + T cells were identified in inflamed intestinal mucosa of patients with Crohn's disease (CD), but not in patients with ulcerative colitis (UC) or healthy controls. These cells shared phenotypic characteristics of Th17 and Treg cells, and showed potent suppressor activity in vitro. Transforming growth factor-® was necessary and sufficient to induce development of a IL17 + FoxP3 + cell population in CD4 + LPLs derived from patients with UC. CONCLUSIONS-The inflammatory environment in the intestinal mucosa of patients with CD contributes to the generation of a distinct population of Treg cells that are FoxP3 + and produce IL-17. These cells are likely to arise during differentiation of Th17 and Treg cells. Specific microenvironmental cues from tissues are likely to determine their commitment to either lineage and affect the balance between regulation and inflammation in the intestine.
Digestive Diseases and Sciences, 2017
Background Hovhannisyan et al. first showed evidence of plasticity between Treg and Th17 in the inflamed intestine of Crohn’s disease (CD) patients. Our previous report suggests that the inflammatory cytokine milieu generates IL-17+Foxp3+CD4+ T lymphocytes which is a crossover population converting Treg subset to Th17 in the peripheral blood of IBD patients. This is considered as an evidence of Treg/Th17 plasticity. Aim The aim of this study was to characterize a variety of helper T cell crossover population, not limited to IL-17+Foxp3+CD4+ T lymphocytes, in the lamina propria (LP) of IBD patients. Methods Fresh colonoscopic biopsies were obtained from patients with CD (n = 50) and ulcerative colitis (UC, n = 32) and from healthy controls (HC, n = 25). LP mononuclear cells were assessed for intracellular cytokines and transcription factors such as IFN𝛾, IL-13, IL-17, IL-22, T-bet, Gata-3, ROR𝛾t, and Foxp3 using multicolor flow cytometry to detect subsets of LP CD4+ T lymphocytes. Results Patients with IBD demonstrated increased cross- over populations in IL-17+ Foxp3+, T-bet+ Foxp3+, Gata3+ Foxp3+, ROR𝛾t+ Foxp3+ populations compared to HC. There was an inverse correlation of Harvey–Bradshaw index with Gata3+ Foxp3+ population in CD patients, while IL-13+ Foxp3+ population was directly correlated with Mayo clinical scores in UC patients. Furthermore, total IL-22 expressing cells as well as Th22 and IL-22+ Th1 populations were decreased in UC compared to CD and HC. Conclusion IBD patients exhibit the increased crossover populations in LP Treg cells toward Th2 and Th17 com- pared to HC. The prevalence of Treg/Th2 crossover pop- ulations is associated with clinical disease score of IBD.
Immunology, 2013
Inflammatory bowel disease (IBD) is characterized by damage to the gut mucosa and systemic inflammation. We sought to evaluate the role of chronic inflammation on circulating T-cell activation in human subjects with Crohn's disease and ulcerative colitis. We studied 54 patients with IBD and 28 healthy controls. T-cell activation and cycling were assessed in whole blood samples by flow cytometry. Levels of lipopolysaccharide (LPS) were measured in serum by Limulus amoebocyte lysate assay, and plasma levels of inflammatory markers and LPS-binding proteins were measured by ELISA. The proportions of circulating CD4 + and CD8 + T lymphocytes in cycle (Ki67 +) are increased in patients with IBD compared with these proportions in controls. CD8 + T cells from patients with IBD are also enriched for cells that expressed CD38 and HLA-DR, and proportions of these cells are related to plasma levels of interleukin-6 and C-reactive protein in these patients. Intracellular interleukin-2 and interferon-c levels were elevated in resting and polyclonally activated CD4 + and CD8 + T cells in patients with IBD when compared with levels from healthy controls. Surprisingly, we did not find increased levels of LPS in the serum of patients with IBD. We did, however, find a signature of recent microbial translocation, as levels of LPS-binding protein are increased in the plasma of patients with IBD compared with plasma levels in healthy controls; LPS-binding protein levels are also directly related to proportions of CD38 HLA-DR-expressing CD4 + and CD8 + T cells. Local damage to the gastrointestinal tract in IBD may result in systemic inflammation and T-cell activation.
Gastroenterology, 2016
BACKGROUND & AIMS: Crohn's disease (CD) has been associated with an altered immune response to commensal microbiota, mostly based on increased seroreactivity to microbial proteins. Although T cells are believed to contribute to the development of CD, little is known about the antigens involved. We investigated the antigen-specificity of T cells isolated from patients with CD. METHODS: We isolated peripheral blood mononuclear cells from 65 patients with CD and 45 healthy individuals (controls). We investigated T-cell reactivity to commensal microbial antigens using proliferation assays (based on thymidine incorporation and carboxyfluorescein succinimidyl ester dilution). Gene expression patterns were determined using microarray and real-time polymerase chain reaction analyses. Cytokines, chemokines, and antibodies were measured by enzyme-linked immunosorbent assay, flow cytometry, or multiplex cytokine assays. Intestinal crypts were obtained from surgical resection specimens of 7 individuals without inflammatory bowel disease. We examined the effects of commensal-specific CD4 þ T cells on primary intestinal epithelial cells from these samples. RESULTS: The bacterial proteins FlaX, A4-fla2, and YidX increased proliferation of CD4 þ T cells isolated from peripheral blood of patients with CD compared with controls. In blood samples from controls, CD4 þ T cells specific for FlaX, A4-fla2, or YidX had a T-helper (Th)1 phenotype; a larger proportion of CD4 þ T cells specific for these proteins in patients with CD had a Th17 phenotype or produced Th1 and Th17 cytokines. When supernatants collected from commensal-specific CD4 þ T cells from patients with CD were applied to healthy intestinal epithelial cells, the epithelial cells increased the expression of the chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL8 and the CC chemokine ligand 20 (CCL20). CONCLUSIONS: A larger proportion of commensalspecific CD4 þ T cells from patients with CD have a Th17 phenotype or produce Th1 and Th17 cytokines, compared with T cells from controls; this might contribute to intestinal inflammation in patients with CD. These cells might be targeted for treatment of CD. The transcriptional data of commensal-specific CD4 þ T cells from healthy individuals and CD patients have been deposited in the Gene Expression Omnibus at the National Center for Biotechnology Information (accession no: GSE70469).
Increased levels of circulating Th17 cells in quiescent versus active Crohn's disease
Journal of Crohn's and Colitis, 2013
Background and aims: Th17 cells, a subset of CD4+ T cells that produce interleukin (IL)-17A, IL-17F, IL-21, IL-22, IL-26, and the chemokine CCL20 are critically involved in the mucosal inflammation observed in Crohn's disease (CD). However, their role as mediators of inflammation in CD has been questioned by a recent clinical trial in which anti-IL-17A (secukinumab) treatment was ineffective. Besides being pro-inflammatory, Th17-related cytokines mediate mucosal protective functions. We aimed to investigate the role of Th17 cells in CD inflammation. Methods: Blood samples from 26 patients with active CD and 10 healthy controls (HC) were analyzed for levels of IL-17A-, IL-21-and IL-22-producing CD45RO+CD4+ T cells using multicolor flow cytometry. Samples were analyzed before and during adalimumab treatment to compare intra-individual changes during active and quiescent disease. Results: CD patients had statistically significantly higher levels of IL-17-A-, IL-21-and IL-22-producing CD45RO+CD4+ T cells in both active and quiescent disease compared with HC. Baseline levels of IL-21 and IL-22 producing CD45RO+CD4+ T cells correlated inversely with mucosal inflammation estimated by fecal calprotectin. Patients who responded to adalimumab treatment demonstrated a 2-to 3-fold increase in levels of IL-17A-and IL-21-producing CD45RO+CD4+ T cells in quiescent disease compared with active disease. Conclusion: Our data support the involvement of Th17 cells and IL-21-and IL-22-producing CD45RO+CD4+ T cells in CD. Because patients had higher levels in quiescent disease compared with active CD, we question whether Th17 cells are promoters of inflammation. Instead, Th17 cells may counterbalance inflammation and maintain gut homeostasis.
Frontiers in Immunology, 2019
The drug targets IL23 and IL12 regulate pathogenicity and plasticity of intestinal Th17 cells in Crohn's disease (CD) and ulcerative colitis (UC), the two most common inflammatory bowel diseases (IBD). However, studies examining Th17 dysregulation in mesenteric lymph nodes (mLNs) of these patients are rare. We showed that in mLNs, CD could be distinguished from UC by increased frequencies of CCR6 + CXCR3 − RORγ + Tbet − CD4 + (Th17) memory T cells enriched in CD62L low effector memory T cells (T EM), and their differentially expressed molecular profile. Th17 T EM cells (expressing IL17A, IL17F, RORC, and STAT3) displayed a higher pathogenic/cytotoxic (IL23R, IL18RAP, and GZMB, CD160, PRF1) gene signature in CD relative to UC, while non-pathogenic/regulatory genes (IL9, FOXP3, CTLA4) were more elevated in UC. In both CD and UC, IL12 but not IL23, augmented IFNγ expression in Th17 T EM and switched their molecular profile toward an ex-Th17 (Th1 *)-biased transcriptomic signature (increased IFNG, and decreased TCF7, IL17A), suggesting that Th17 plasticity occurs in mLNs before their recruitment to inflamed colon. We propose that differences observed between Th17 cell frequencies and their molecular profile in CD and UC might have implications in understanding disease pathogenesis, and thus, therapeutic management of patients with IBD.
Frequency of CD4+CD161+ T Cell and Interleukin-10 Expression in Inflammatory Bowel Diseases
Acta Histochemica et Cytochemica
Mucosal immune dysregulation associated with T cells plays a critical role in the development of inflammatory bowel diseases (IBD). However, the definite significances of these cells in IBD still remain unclear. Therefore, we investigated the population and expression of CD4 + CD161 + T cells in the colonic lamina propria mononuclear cells (LPMCs) in patients with IBD by analyses using flow cytometry and immunohistochemistry. Interleukin-10 (IL-10) mRNA levels in both LPMCs and CD4 + T cells in lamina propria (LP-CD4 + T cells) were measured using a real-time quantitative reverse transcription-polymerase chain reaction. IL-10 production was investigated with immunohistochemistry. The results revealed that the population of CD4 + CD161 + T cells was significantly decreased in active ulcerative colitis (UC) compared with inactive UC (P < 0.05). The CD4 + CD161 + T cell population was inversely correlated with disease activity in patients with UC (r = −0.6326, P = 0.0055), but there was no significant correlation in those with Crohn's disease. Overexpression of IL-10 mRNA in both LPMCs and LP-CD4 + T cells were detected in active UC. Immunohistochemistry revealed decreased frequency of CD161 + cells and increased IL-10 positive cells in active UC. The frequency of CD4 + CD161 + T cells and IL-10 expression was supposed to be associated with the pathological status of mucosal immunoregulation in IBD.
Inflammatory Bowel Diseases, 2008
Background: Interleukin (IL)-17F, produced in IL-23R-expressing Th17 cells, is a novel member of the IL-17 cytokine family. Given the association of IL23R with inflammatory bowel disease (IBD), we characterized the role of IL-17F in IBD including its intestinal gene expression and the effect of the IL17F p.His161Arg polymorphism on disease susceptibility and phenotype of Crohn's disease (CD) and ulcerative colitis (UC). In addition, we analyzed the IL17F p.His161Arg polymorphism for potential epistasis with IL23R and NOD2/CARD15 variants. Methods: Intestinal IL-17F mRNA expression was measured by quantitative polymerase chain reaction (PCR). Genomic DNA from 1682 individuals (CD: n ϭ 499; UC: n ϭ 216; controls: n ϭ 967) was analyzed for the presence of the IL17F p.His161Arg polymorphism, the 3 NOD2 variants, p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008, and 10 CD-associated IL23R variants. Results: Intestinal IL-17F mRNA expression was 4.4-fold increased in inflamed colonic lesions compared to uninflamed biopsies in CD (P ϭ 0.016) but not in UC. However, the mean intestinal IL-17F mRNA expression was higher in UC than in CD (P Ͻ 0.0001). The IL17F p.His161Arg substitution was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype, but weakly associated with a low body mass index (BMI; P ϭ 0.009) and an earlier age of disease onset (P ϭ 0.039) in UC. There was no evidence for epistasis between the IL17F p.His161Arg polymorphism and IBDassociated single nucleotide polymorphisms within the IL23R gene. Conclusions: Intestinal IL17F gene expression is increased in active CD. The IL17F p.His161Arg polymorphism is not associated with IBD susceptibility and has no epistatic interaction with CDassociated IL23R variants.