IL-17A-Producing Foxp3⁺ Regulatory T Cells and Human Diseases

CD4⁺Foxp3⁺ regulatory T (Treg) cells play major roles in immune homeostasis. While CD4⁺Foxp3⁺ Treg cells act to suppress other immune effector cells, there is growing evidence that they also produce pro-inflammatory cytokines, such as IL-17A, in inflammatory conditions. The pro-inflammatory cytokine milieu, toll-like receptor (TLR) signaling, and specific transcription factors are important for the production of IL-17A by CD4⁺Foxp3⁺ Treg cells. In particular, IL-17A-producing CD4⁺Foxp3⁺ Treg cells express RORγt, the T helper (Th) 17-specific transcription factor, in addition to Foxp3. IL-17A-producing CD4⁺Foxp3⁺ Treg cells are also involved in the pathogenesis of various diseases. Here we review the mechanisms underlying the induction of IL-17A-producing CD4⁺Foxp3⁺ Treg cells and the roles of these cells in human disease.

Potential Utility of FDG PET-CT as a Non-invasive Tool for Monitoring Local Immune Responses

PURPOSE: The tumor microenvironment is known to be associated with the metabolic activity of cancer cells and local immune reactions. We hypothesized that glucose metabolism measured by 2-deoxy-2-(¹⁸F)fluoro-D-glucose (¹⁸F-FDG) positron emission tomography (PET)-computed tomography (CT) (¹⁸F-FDG PET-CT) would be associated with local immune responses evaluated according to the presence of tumor infiltrating lymphocytes (TILs). MATERIALS AND METHODS: We retrospectively reviewed 56 patients who underwent ¹⁸F-FDG PET-CT prior to gastrectomy. In resected tumor specimens, TIL subsets, including cluster of differentiation (CD) 3, CD4, CD8, Forkhead box P3 (Foxp3), and granzyme B, were subjected to immunohistochemical analysis. The prognostic nutritional index (PNI) was calculated as: (10×serum albumin value)+(0.005×peripheral lymphocyte counts). Additionally, the maximum standard uptake value (SUVmax) was calculated to evaluate the metabolic activity of cancer cells. RESULTS: The SUVmax was positively correlated with larger tumor size (R=0.293; P=0.029) and negatively correlated with PNI (R=−0.407; P=0.002). A higher SUVmax showed a marginal association with higher CD3 (+) T lymphocyte counts (R=0.227; P=0.092) and a significant association with higher Foxp3 (+) T lymphocyte counts (R=0.431; P=0.009). No other clinicopathological characteristics were associated with SUVmax or TILs. Survival analysis, however, indicated that neither SUVmax nor Foxp3 held prognostic significance. CONCLUSIONS: FDG uptake on PET-CT could be associated with TILs, especially regulatory T cells, in gastric cancer. This finding may suggest that PET-CT could be of use as a non-invasive tool for monitoring the tumor microenvironment in patients with gastric cancer.

Relationship between percentage of regulatory t-cells and dental amalgam fillings / Relación entre el porcentaje de células t-reguladoras y obturaciones de amalgama

Abstract: introduction: regulatory T-cells are the main component of peripheral tolerance and their level is decreased in autoimmunity. In dental amalgam, a mixture of metals is used as a restorative material. During daily a ctivities, these metals are ingested and affect renal, neurosensory and immune systems. Studies have demonstrated an increased risk of autoimmune diseases in patients with dental amalgam fillings. It was hypothesized that the percentage of regulatory T-cells decreases in individuals with amalgam fillings. Therefore this study was designed to determine and compare the percentage of regulatory T-cells in individuals with and without amalgam fillings. Material and Methods: This was a cross-sectional study. Subjects were divided into two groups with each group consisting of 40 individuals. Group I (study group) comprised individuals with amalgam fillings, and Group II (control group), individuals without amalgam fillings in their teeth. Blood samples of all the participants were collected and tagged with CD4 FITC, CD25 PE and CD127 PerCP-Cy monoclonal antibodies for the detection of regulatory T-cells, FACSCalibur was used for this purpose. Results: The percentage of regulatory T-cells in the control group was high (77.77 +/- 5.54 percent) compared to the study group (76.09 +/- 7.68 percent), however, on comparison, the difference was not statistically significant (p=0.25). Conclusion: Dental amalgam fillings did not show a declining effect on the percentage of regulatory T-cells.

Resumen: introducción: las células T reguladoras son el principal componente de la tolerancia periférica y su nivel se reduce en la autoinmunidad. En las obturaciones de amalgama, una mezcla de metales se utiliza como un material de restauración. Durante las actividades diarias, estos metales se ingieren y afectan el sistema renal, neurosensorial e inmunológico. Los estudios han demostrado un aumento del riesgo de enfermedades autoinmunes en pacientes con amalgamas dentales. Se planteó la hipótesis que el porcentaje de células T reguladoras disminuye en individuos con obturaciones de amalgama. Por tanto, este estudio fue diseñado para determinar y comparar el porcentaje de células T reguladoras en individuos con y sin obturaciones de amalgama. Material y Métodos: Se realizó un estudio de corte transversal. Los sujetos fueron divididos en dos grupos, cada uno con 40 individuos. El grupo I (de estudio) estuvo conformado por individuos con obturaciones de amalgama y el grupo II (de control) por individuos sin obturaciones de amalgma. Se colectaron muestras de sangre, las que fueron marcadas con anticuerpos monoclonales CD4 FITC, CD25 PE y CD127 PerCP-C para detectar las células T reguladoras, se utilizó FACSCalibur para este propósito. Resultados: El porcentaje de células T reguladoras en el grupo control fue alta (77,77 +/- 5,54 por ciento) en comparación con el grupo de estudio (76,09 +/- 7,68 por ciento), pero esta diferencia no fue estadísticamente significativa (p=0,25). Conclusión: Las obturaciones de amalgama no se asociaron con una disminución en el porcentaje de células T reguladoras.

Changes in inducible IL-35-producing regulatory T cells in children with acute Kawasaki disease and their significance / 中华实用儿科临床杂志

Objective To investigate the changes and significances of inducible IL-35-producing regulatory T cells(iTR35) in immunological pathogcnesis of Kawasaki disease (KD).Methods Forty-eight children with KD and 32 age-matched healthy children (healthy control group) consented to participate in this study.Flow cytometry was performed to evaluate the proportions of CD4+ FOXP3-IL-12p35+IL-27EBI3+iTR35 and CD4+CD25high FOXP3+regulatory T cells (Treg),and expression levels of associated molecules such as programmed death-ligand 1 (PD-L1),CD169,programmed death 1 (PD-1),CD43,IL-12p35,Epstein-Barr virus induced 3 (IL-27EBI3),glycoprotein 130(gp130),IL-12 receptor beta 2 (IL-12Rβ2),phosphated signal transducer and activator of transcription 1 (pSTAT1) and phosphated signal transducer and activator of transcription 4 (pSTAT4).Transcription levels of the Sre homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2),phosphatase and tensin homolog (PTEN),Vavl guanine nucleotide exchange factor(Vav) in CD4+T cells were determined by quantitative real-time PCR.Plasma concentrations of IL-35,IL-10,TNF-α and IL-12 were measured by enzyme-linked immunosorbent assay.Results (1) The proportions of iTR35 and its expressions of IL-12p35 and IL-27EBI3 in patients with acute KD dccreased remarkably[iTR35:(0.72±0.26) ‰ vs (1.65±0.43) ‰,P＜0.05],and restored after treatment [iTR35:(1.58±0.63) ‰ vs (0.72±0.26) ‰,P＜0.05].(2) The proportions of Treg and transcriptional levels of IL-12p35 and IL-27EBI3 were down-regulated during acute phase of KD [Treg:(3.26±1.21) ％ vs (7.26±2.86) ％,P＜0.05],and increased to some extent after therapy [Treg:(5.89±2.60)％ vs (3.26±1.21)％,P＜0.05].Meanwhile,plasma concentrations of IL-35 and IL-10,and expressions of gp130,IL-12Rβ2,pSTAT1 and pSTAT4 in iTR35 of patients with acute KD were found lower than those of the healthy control group (all P＜0.05),and increased after treatment (P＜0.05).Additionally,positive correlations were found between plasma concentrations of IL-35 and the proportion of iTR35 or its expressions of IL-12p35 and IL-27EBI3,respectively.(3) Expressions of PD-L1 and CD169 on CD14 + cells and plasma concentrations of TNF-α and IL-12 were elevated significantly during acute KD(all P＜0.05),as well as expression levels of the ligands (PD-1 and CD43) and its downstream molecules (SHP-2,PTEN,Vav) in CD4 + T cells were found to be lower in patients with acute KD (P＜0.05),and restored remarkably after therapy.Conclusion Insufficiency of iTR35 and its expression of IL-35 might be one of the important factors contributing to immunological dysfunction in KD.

Toxoplasma gondii Infection Suppresses House Dust Mite Extract-Induced Atopic Dermatitis in NC/Nga Mice

PURPOSE: Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that infects humans and animals via congenital or postnatal routes, and it is found worldwide. Modulation of the immune system by parasite infection is proposed to suppress allergic inflammation. Growing evidences have shown that interleukin (IL)-10-producing regulatory B cells (B(regs)) and CD4+CD25+FoxP3+ regulatory T cells (T(regs)) induced by parasite infection play a critical role in allergic or autoimmune diseases because these cells regulate negatively cellular immune responses and inflammation. Currently, the role of IL-10-producing regulatory B cells in host immune response during T. gondii infection is unknown. In this study, we investigate whether T. gondii infection can suppress the development of unrelated atopic dermatitis (AD)-like lesions. METHODS: AD is a chronically relapsing inflammatory skin disease accompanied by severe itching; for this, we used NC/Nga mice, a well-known experimental model of systemic AD. Repeated exposure to Dermatophagoides farinae crude extract (DfE), known as a major environmental allergen, evokes AD-like skin lesions in NC/Nga mice under specific pathogen-free conditions. NC/Nga mice were intraperitoneally infected with 10 cysts of T. gondii. RESULTS: T. gondii infection significantly ameliorated AD-like skin lesions in NC/Nga mice. The subpopulation of B(regs) and T(regs) in the AD mice was expanded in the course of T. gondii infection. In addition, T. gondii infection inhibited Th2 and enhanced Th1 immune response in the DfE-treated AD mice. CONCLUSIONS: We have experimentally demonstrated for the first time that T. gondii infection ameliorated AD-like skin lesions in a mouse model of AD. Our study could in part explain the mechanisms of how parasite infection prevents the development of allergic disorder. Therefore, these immunemechanisms induced by T. gondii infection may be beneficial for the host in terms of reduced risk of allergic immune reactions.

CD4+CD25highFoxP3+ Regulatory T-cells in Hematologic Diseases / 대한진단검사의학회지

BACKGROUND: CD4+CD25+ regulatory T-cells (Tregs) play a critical role in immune responses. We explored the status of Tregs in neoplastic and autoimmune hematologic diseases. We also evaluated the technical aspects of Treg measurement in terms of sample type and detection markers. METHODS: A total of 68 subjects were enrolled: 11 with AML, 8 with MDS, 10 with autoimmune diseases, and 39 controls. Tregs were analyzed in peripheral blood (PB) and bone marrow (BM) samples from each subject. Flow cytometry and the Human Regulatory T cell Staining Kit (eBioscience, USA) for CD4, CD25, and FoxP3 (forkhead box P3) were used. RESULTS: The CD4+CD25high/CD4 and CD4+CD25highFoxP3+/CD4 populations were significantly correlated (P<0.0001). The AML and high-risk MDS groups had significantly larger CD4+CD25high/CD4 and CD4+CD25highFoxP3+/CD4 populations in PB than the autoimmune (P=0.007 and 0.012, respectively) and control groups (P=0.004 and 0.006, respectively). Comparable findings were observed in BM. The CD4+CD25highFoxP3+/CD4 population was significantly larger in PB than in BM (P=0.0003). CONCLUSIONS: This study provides comparison data for Tregs in AML, MDS, and autoimmune hematologic diseases, and would be helpful for understanding the different immunologic bases of various hematologic diseases. Treg measurement using CD4, CD25, and/or FoxP3 in PB rather than in BM seems to be practical for routine hematologic purposes. Large-scale analysis of the diagnostic role of Treg measurement is needed.

Inmunidad y Helicobacter pylori / Immunity and Helicobacter pylori

Helicobacter pylori, es una bacteria Gram negativa que coloniza la mucosa gástrica y contribuye al desarrollo de patologías como la gastritis crónica, úlceras duodenales y en menor medida cáncer gástrico. Si bien la infección por H. pylori por sí sola es capaz de producir daño al epitelio gástrico a través de la expresión de numerosos factores de virulencia, es la respuesta inmune local la mayor responsable de la patogenia de las enfermedades asociadas a dicha infección. La clásica dicotomía en la respuesta T helper tipo 1 vs tipo 2 para explicar el daño asociado a la bacteria, ha dado paso a un escenario más complejo con la reciente descripción de las células T regulatorias y la existencia de nuevos perfiles de respuesta T helper como Th 17. El delicado equilibrio entre virulencia y respuesta infl amatoria inmune es principalmente regulado por la intensidad de la respuesta T regulatoria, cuya supresión permite la expresión de una respuesta efectora potencialmente responsable del daño final.

Helicobacter pylori a Gram negative bacterium that colonizes gastric mucosa and that has been associated to different disease such as chronic gastritis, duodenal ulcers and gastric cancer. Although the infection by itself is able to produce damage to the gastric mucosa through the expression and interaction of well-known virulence factors, the immune local response is strongly involved in the pathogenesis of H. pylori-associated diseases. The classic dichotomy T helper type 1 vs type 2 response to explain the damage associated to the bacterium, has been reevaluated in a more complex scenario with the recent description of the T regulatory response and the new patterns of T helper response such as Th17. The extremely well balanced equilibrium between virulence and immune inflammatory response is mainly regulated by the intensity of the T regulatory response; its suppression would allow the expression of different T helper responses that account for the final damage and clinical outcomes.

Innate immunity and regulatory T-cells in human Chagas disease: what must be understood?

There is a general consensus that during chronic Trypanosoma cruzi infection, the host immune system induces complex processes to ensure the control of parasite growth while preserving the potential to mount and maintain a life-long controlled humoral and cellular immune response against the invading pathogen. This review summarises evidence in an attempt to elucidate "what must be understood" to further clarify the role of innate immunity in the development/maintenance of clinical Chagas disease and the impact of etiological treatment on host immunity, highlighting the contributions of the innate immunity and regulatory T (Treg) cells. Recently, increasing focus on innate immunity suggest that chronic T. cruzi infection may cause morbidity when innate effector functions, or the down-regulation of adaptive regulatory mechanisms are lacking. In this context, stable asymptomatic host-parasite interactions seem to be influenced by the effector/regulatory balance with the participation of macrophages, natural killer (NK) and CD8+ T cells in parallel with the establishment of regulatory mechanisms mediated by NKT and Treg cells. Moreover, a balanced innate immune activation state, apart from Treg cells, may play a role in controlling the adverse events triggered by the massive antigen release induced by trypanosomicidal agents during Chagas disease etiological treatment.

Expression of regulatory T cells and helper T cells in human IgA nephropathy and its significance / 中华肾脏病杂志

Objective To investigate the effects of CD4+CD25high regulatory T cells(Treg)and the imbalance of helper T lymphocyte subsets(Th1/Th2)on the immunological mechanism of IgA nephropathy(IgAN)patients. Methods The percentage of Treg and helper T cells subpopulation (Th1/Th2)in the peripheral blood of IgAN patients and healthy controls was examined by flow cytometry.The FOXP3 expression was detected through intracellular staining.The correlation of Treg or Th1/Th2 with clinical parameters of IgAN was analyzed by Spearman or Pearson rank correlation test. Results The percentages of Treg and Th2 cells were significantly higher in peripheral blood of IgAN patients compared to that of healthy controls[Treg (2.14±0.82)%vs[1.59±0.53)%,Th2(2.57±0.72)%vs(1.81±1.10)%,all P＜0.05].Th1/Th2 ratio was significantly reduced in IgAN patients(5.75±1.89 vs 12.73±9.79,P＜0.05).The percentage of circulating Treg cells was positively correlated with serunl IgA concentration(r=0.397,P＜0.05),and was negatively correlated with eGFR(r=-0.376,P＜0.05).The percentage of circulating Th2 cells was positively correlated with serum IgA(r=0.468,P＜0.05). Conclusions There is a disorder of T lymphocyte population in the peripheral blood of IgAN patients.The increased Treg and Th2 cells may play an important role in the pathogenesis of IgAN.