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Fulltext Depletion of regulatory T-cells leads to moderate B-cell antigenicity in respiratory syncytial virus infection

Shao HY, Huang JY, Lin YW, Yu SL, Chitra E, Chang CK, et al.

Int J Infect Dis, 2015 Dec;41:56-64.
PMID: 26555647 DOI: 10.1016/j.ijid.2015.10.026

The regulation of the immunopathology of respiratory syncytial virus (RSV) by regulatory T-cells (CD4(+)CD25(+)Foxp3(+); Tregs) is not understood.

Matched MeSH terms: T-Lymphocytes, Regulatory
Fulltext The role of TNFR2+ Tregs in COVID-19: An overview and a potential therapeutic strategy

Ahmad S, Hatmal MM, Lambuk L, Al-Hatamleh MAI, Alshaer W, Mohamud R

Life Sci, 2021 Dec 01;286:120063.
PMID: 34673116 DOI: 10.1016/j.lfs.2021.120063

COVID-19 is a multi-faceted disease ranging from asymptomatic to severely ill condition that primarily affects the lungs and could advance to other organs as well. It's causing factor, SARS-CoV-2 is recognized to develop robust cell-mediated immunity that responsible to either control or exaggerate the infection. As an important cell subset that control immune responses and are significantly dysregulated in COVID-19, Tregs is proposed to be considered for COVID-19 management. Among its hallmark, TNFR2 is recently recognized to play important role in the function and survival of Tregs. This review gathers available TNFR2 agonists to directly target Tregs as a potential approach to overcome immune dysregulation that affect the severity in COVID-19. Furthermore, this review performs a rigid body docking of TNF-TNFR2 interaction and such interaction with TNFR2 agonist to predict the optimal targeting approach.

Matched MeSH terms: T-Lymphocytes, Regulatory/immunology*
Aberrant frequency of TNFR2-expressing CD4+ FoxP3+ regulatory T cells in nasopharyngeal carcinoma patients

Engku Abd Rahman ENS, Irekeola AA, Shueb RH, Mat Lazim N, Mohamud R, Chen X, et al.

Cytokine, 2023 Oct;170:156341.
PMID: 37657236 DOI: 10.1016/j.cyto.2023.156341

TNFR2 is a surface marker of highly suppressive subset of CD4+ FoxP3+ regulatory T cells (Tregs) in humans and mice. This study examined the TNFR2 expression by Tregs of nasopharyngeal carcinoma (NPC) patients and healthy controls. The proliferation, migration, survival of TNFR2+ Tregs, and association with clinicopathological characteristics were assessed. The expression levels of selected cytokines were also determined. The results demonstrated that in both peripheral blood (PB) (10.45 ± 5.71%) and tumour microenvironment (TME) (54.38 ± 16.15%) of NPC patients, Tregs expressed TNFR2 at noticeably greater levels than conventional T cells (Tconvs) (3.91 ± 2.62%, p 0.05), the proportions of PB and TME TNFR2+ Tregs in NPC patients showed more proliferative, higher migration capacity, and better survival ability, as compared to those in healthy controls. Furthermore, TNFR2+ Tregs from NPC patients expressed significantly higher amounts of IL-6 (p = 0.0077), IL-10 (p = 0.0001), IFN-γ (p = 0.0105) and TNF-α (p

Matched MeSH terms: T-Lymphocytes, Regulatory*
Carica papaya increases regulatory T cells and reduces IFN-γ+ CD4+ T cells in healthy human subjects

Abdullah M, Chai PS, Loh CY, Chong MY, Quay HW, Vidyadaran S, et al.

Mol Nutr Food Res, 2011 May;55(5):803-6.
PMID: 21520494 DOI: 10.1002/mnfr.201100087

Fruit and vegetables have therapeutic potential as they dampen inflammation, have no known side-effects and as whole foods have prospective additive and synergistic benefits. Th1 (IFN-γ(+) CD4(+))/Th2 (IL-4(+)CD4(+)) T cells play a vital role in mediating inflammatory responses and may be regulated by regulatory T cells (Tregs). Effects of Carica papaya on cells of healthy individuals were determined using flow cytometry methods. Significant down-regulation of IFN-γ(+) CD4(+) (p=0.03, n=13), up-regulation of IL-4(+) CD4(+) (p=0.04, n=13) T cells and up-regulation of CD3(+) CD4(+) CD25(+) CD127(-) (p=0.001, n=15) Tregs were observed after papaya consumption. In vitro cultures showed up-regulation of Tregs in male subjects and was significantly associated with levels of IL-1β in culture supernatants (R(2) =0.608, p=0.04, n=12). Other inflammatory cytokines were significantly suppressed. Papaya consumption may exert an anti-inflammatory response mediated through Tregs and have potential in alleviating inflammatory conditions.

Matched MeSH terms: T-Lymphocytes, Regulatory/drug effects*; T-Lymphocytes, Regulatory/immunology
Fulltext Tropomyosin Receptor Kinase C Targeted Delivery of a Peptidomimetic Ligand-Photosensitizer Conjugate Induces Antitumor Immune Responses Following Photodynamic Therapy

Kue CS, Kamkaew A, Voon SH, Kiew LV, Chung LY, Burgess K, et al.

Sci Rep, 2016 11 17;6:37209.
PMID: 27853305 DOI: 10.1038/srep37209

Tropomyosin receptor kinase C (TrkC) targeted ligand-photosensitizer construct, IYIY-diiodo-boron-dipyrromethene (IYIY-I2-BODIPY) and its scrambled counterpart YIYI-I2-BODIPY have been prepared. IYIY-I2-BODIPY binds TrkC similar to neurotrophin-3 (NT-3), and NT-3 has been reported to modulate immune responses. Moreover, it could be shown that photodynamic therapy (PDT) elevates antitumor immune responses. This prompted us to investigate the immunological impacts mediated by IYIY-I2-BODIPY in pre- and post-PDT conditions. We demonstrated that IYIY-I2-BODIPY (strong response) and YIYI-I2-BODIPY (weak response) at 10 mg/kg, but not I2-BODIPY control, increased the levels of IL-2, IL-4, IL-6 and IL-17, but decreased the levels of systemic immunoregulatory mediators TGF-β, myeloid-derived suppressor cells and regulatory T-cells. Only IYIY-I2-BODIPY enhanced the IFN-γ+ and IL-17+ T-lymphocytes, and delayed tumor growth (~20% smaller size) in mice when administrated daily for 5 days. All those effects were observed without irradiation; when irradiated (520 nm, 100 J/cm2, 160 mW/cm2) to produce PDT effects (drug-light interval 1 h), IYIY-I2-BODIPY induced stronger responses. Moreover, photoirradiated IYIY-I2-BODIPY treated mice had high levels of effector T-cells compared to controls. Adoptive transfer of immune cells from IYIY-I2-BODIPY-treated survivor mice that were photoirradiated gave significantly delayed tumor growth (~40-50% smaller size) in recipient mice. IYIY-I2-BODIPY alone and in combination with PDT modulates the immune response in such a way that tumor growth is suppressed. Unlike immunosuppressive conventional chemotherapy, IYIY-I2-BODIPY can act as an immune-stimulatory chemotherapeutic agent with potential applications in clinical cancer treatment.

Matched MeSH terms: T-Lymphocytes, Regulatory/immunology*; T-Lymphocytes, Regulatory/pathology
Fulltext A tryptophan metabolite made by a gut microbiome eukaryote induces pro-inflammatory T cells

Wojciech L, Png CW, Koh EY, Kioh DYQ, Deng L, Wang Z, et al.

EMBO J, 2023 Nov 02;42(21):e112963.
PMID: 37743772 DOI: 10.15252/embj.2022112963

The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host-microbiome coexistence depends largely on the balance between regulators and responder intestinal CD4+ T cells. We found that ulcerative colitis-like changes in the large intestine after infection with the protist Blastocystis ST7 in a mouse model are associated with reduction of anti-inflammatory Treg cells and simultaneous expansion of pro-inflammatory Th17 responders. These alterations in CD4+ T cells depended on the tryptophan metabolite indole-3-acetaldehyde (I3AA) produced by this single-cell eukaryote. I3AA reduced the Treg subset in vivo and iTreg development in vitro by modifying their sensing of TGFβ, concomitantly affecting recognition of self-flora antigens by conventional CD4+ T cells. Parasite-derived I3AA also induces over-exuberant TCR signaling, manifested by increased CD69 expression and downregulation of co-inhibitor PD-1. We have thus identified a new mechanism dictating CD4+ fate decisions. The findings thus shine a new light on the ability of the protist microbiome and tryptophan metabolites, derived from them or other sources, to modulate the adaptive immune compartment, particularly in the context of gut inflammatory disorders.

Matched MeSH terms: T-Lymphocytes, Regulatory
Increased regulatory T cells in acute lymphoblastic leukaemia patients

Idris SZ, Hassan N, Lee LJ, Md Noor S, Osman R, Abdul-Jalil M, et al.

Hematology, 2016 May;21(4):206-12.
PMID: 26907959 DOI: 10.1080/10245332.2015.1101965

INTRODUCTION: Regulation in adaptive immune response balances a fine line that prevents instigation of self-damage or fall into unresponsiveness permitting abnormal cell growth. Mechanisms that keep this balance in check include regulatory T cells (Tregs). Tregs consist of a small but heterogeneous population, which may be identified by the phenotype, CD3+CD4+CD25+CD127-. The role of Tregs in pathogenesis of cancers is thus far supported by evidence of increased Tregs in various cancers and may contribute to poorer prognosis. Tregs may also be important in acute leukaemias.
OBJECTIVE: A review of the literature on Tregs in acute leukaemias was conducted and Tregs were determined in B-cell acute lymphoblastic leukaemias (ALLs).
RESULTS: Studies on Tregs in B-cell ALL are few and controversial. We observed a significantly increased percentage of Tregs (mean±SD, 9.72 ± 3.79% vs. 7.05 ± 1.74%; P = 0.047) in the bone marrow/peripheral blood of ALL (n = 17) compared to peripheral blood of normal controls (n = 35). A positive trend between Tregs and age (R = 0.474, P = 0.055, n = 17) implicates this factor of poor prognosis in B-cell ALL.
DISCUSSION: Tregs in cancer are particularly significant in immunotherapy. The manipulation of the immune system to treat cancer has for a long time ignored regulatory mechanisms inducible or in place. In lymphoma studies, tumour-specific mechanisms that are unlike conventional methods in the induction of Tregs have been hypothesized. In addition, tumour-infiltrating Tregs may present different profiles from peripheral blood pictures. Tregs will continue to be dissected to reveal its mysteries and their impact on clinical significance.

Matched MeSH terms: T-Lymphocytes, Regulatory/immunology*
Targeting immunosuppressor cells with nanoparticles in autoimmunity: How far have we come to?

Ahmad S, Al-Hatamleh MAI, Mohamud R

Cell Immunol, 2021 10;368:104412.
PMID: 34340162 DOI: 10.1016/j.cellimm.2021.104412

Autoimmunity is the assault of immune response towards self-antigens, resulting to inflammation and tissue injury. It is staged into three phases and caused by malfunction of immune tolerance. In our body, immune tolerance is synchronized by several immunosuppressor cells such as regulatory T cells and B cells as well as myeloid-derived suppressor cells, which are prominently dysregulated in autoimmunity. Hence, targeting these cell populations serve as a significant potential in the therapy of autoimmunity. Nanotechnology with its advantageous properties is shown to be a remarkable tool as drug delivery system in this field. This review focused on the development of therapeutics in autoimmune diseases utilizing various nanoparticles formulation based on two targeting approaches in autoimmunity, passive and active targeting. Lastly, this review outlined the approved present nanomedicines as well as in clinical evaluations and issues regarding the lack of translation of these nanomedicines into the market, despite the abundant of positive experimental observations.

Matched MeSH terms: T-Lymphocytes, Regulatory/immunology*
Application of Ti3 C2 MXene Quantum Dots for Immunomodulation and Regenerative Medicine

Rafieerad A, Yan W, Sequiera GL, Sareen N, Abu-El-Rub E, Moudgil M, et al.

Adv Healthc Mater, 2019 08;8(16):e1900569.
PMID: 31265217 DOI: 10.1002/adhm.201900569

Inflammation is tightly linked to tissue injury. In regenerative medicine, immune activation plays a key role in rejection of transplanted stem cells and reduces the efficacy of stem cell therapies. Next-generation smart biomaterials are reported to possess multiple biologic properties for tissue repair. Here, the first use of 0D titanium carbide (Ti3 C2 ) MXene quantum dots (MQDs) for immunomodulation is presented with the goal of enhancing material-based tissue repair after injury. MQDs possess intrinsic immunomodulatory properties and selectively reduce activation of human CD4+ IFN-γ+ T-lymphocytes (control 87.1 ± 2.0%, MQDs 68.3 ± 5.4%) while promoting expansion of immunosuppressive CD4+ CD25+ FoxP3+ regulatory T-cells (control 5.5 ± 0.7%, MQDs 8.5 ± 0.8%) in a stimulated lymphocyte population. Furthermore, MQDs are biocompatible with bone marrow-derived mesenchymal stem cells and induced pluripotent stem cell-derived fibroblasts. Finally, Ti3 C2 MQDs are incorporated into a chitosan-based hydrogel to create a 3D platform with enhanced physicochemical properties for stem cell delivery and tissue repair. This composite hydrogel demonstrates increased conductivity while maintaining injectability and thermosensitivity. These findings suggest that this new class of biomaterials may help bridge the translational gap in material and stem cell-based therapies for tissue repair and treatment of inflammatory and degenerative diseases.

Matched MeSH terms: T-Lymphocytes, Regulatory/drug effects; T-Lymphocytes, Regulatory/metabolism
Fulltext A Perspective Review on the Role of Nanomedicine in the Modulation of TNF-TNFR2 Axis in Breast Cancer Immunotherapy

Al-Hatamleh MAI, Ahmad S, Boer JC, Lim J, Chen X, Plebanski M, et al.

J Oncol, 2019;2019:6313242.
PMID: 31239840 DOI: 10.1155/2019/6313242

In the past decade, nanomedicine research has provided us with highly useful agents (nanoparticles) delivering therapeutic drugs to target cancer cells. The present review highlights nanomedicine applications for breast cancer immunotherapy. Recent studies have suggested that tumour necrosis factor (TNF) and its receptor 2 (TNFR2) expressed on breast cancer cells have important functional consequences. This cytokine/receptor interaction is also critical for promoting highly immune-suppressive phenotypes by regulatory T cells (Tregs). This review generally provides a background for nanoparticles as potential drug delivery agents for immunomodulators and further discusses in depth the potential of TNF antagonists delivery to modulate TNF-TNFR2 interactions and inhibit breast cancer progression.

Matched MeSH terms: T-Lymphocytes, Regulatory
Major depressive disorder patients on antidepressant treatments display higher number of regulatory T cells

Mohd Ashari NS, Mohamed Sanusi SNF, Mohd Yasin MA, Che Hussin CM, Wong KK, Shafei MN

Malays J Pathol, 2019 Aug;41(2):169-176.
PMID: 31427552

INTRODUCTION: Regulatory T cell (Treg) is a subtype of T lymphocyte that plays a crucial role in establishing immunologic self-tolerance and maintaining immune homeostasis. In this study, we set out to investigate the percentage and absolute count of Tregs in major depressive disorder (MDD) patients and their correlation with disease severity.
MATERIALS & METHODS: This is a case-control study consisting of 47 MDD patients and 47 healthy controls. MDD patients were treated with antidepressant drugs according to their physician's choice. The severity of MDD was assessed using Beck Depression Inventory (BDI) and Montgomery-Asberg Depression Rating Scale (MADRS) at the time of recruitment. Healthy controls completed the Depression Anxiety Scoring System (DASS21) questionnaire to ensure they were in good mental health without history of MDD. The percentage and absolute count of CD4+ CD25+ Tregs and CD4+ CD25+ FOXP3+ Tregs were identified by multiparameter flow cytometry.
RESULTS: The percentage and absolute count of CD4+ CD25+ Treg cells were significantly higher in MDD patients than in healthy controls (P<0.001, in both cases). Likewise, the percentage and absolute count of CD4+ CD25+ FOXP3+ Treg cells were also significantly higher in MDD patients compared to healthy controls (P=0.003 and P=0.002, respectively). However, there was no significant correlation between the percentage and absolute count of CD4+ CD25+ Treg and CD4+ CD25+ FOXP3+ Treg cells with BDI or MADRS score.
CONCLUSIONS: Our results suggest that antidepressant treatments contributed to an upregulation of Tregs in MDD patients.

Matched MeSH terms: T-Lymphocytes, Regulatory
Fulltext Cancer immunotherapy: current progress and applications

Pooi, Pooi Leong, Heng, Fong Seow

Malaysian Journal of Medicine and Health Sciences, 2006;2(2):1-26.
MyJurnal

Cancer immunotherapy is a form of treatment protocol for cancer patients that has been studied intensively over the last two decades. The undesirable side effects during the course of conventional treatment has lead to the development of immunotherapy as an alternative treatment modality. This approach encompasses the use of three different strategies with various immunotherapeutic modalities including (i) cytokines and monoclonal antibodies; (ii) activation of antigen presentation cells (APC) by using antigen-specific peptides or sources of antigens such as tumour lysate; and finally (iii) adoptive transfer of ex vivo activated autologous cytotoxic T-cells. Due to specific-targeting by antigen-specific monoclonal antibodies, dendritic cells and activated CD8+ T-cells, immunotherapy can eliminate tumour
cells efficiently but the normal tissues are unaffected. Despite years of investigation, the outcome of immunotherapy-based clinical trials are inconsistent with very low response rates from patients. Several mechanisms have been proposed to contribute to this failure including the presence of regulatory T-cells (Treg), immunomodulatory cytokines, and aberrant gene expression in tumour cells. This review summarises information from about 140 articles and review papers. In addition, it also provides an update on recent trends in combinational immunotherapy with conventional therapy and encouraging results have been obtained. Reevaluation of previous studies is necessary to fine-tune the design and approach of immunotherapy to ensure better treatment outcomes.

Matched MeSH terms: T-Lymphocytes, Regulatory
Fulltext Technical Considerations in Ex Vivo Human Regulatory T Cell Migration and Suppression Assays

Irekeola AA, E A R ENS, Lazim NM, Mohamud R, Yean CY, Shueb RH

Cells, 2020 02 20;9(2).
PMID: 32093265 DOI: 10.3390/cells9020487

Regulatory T cells (Tregs) are renowned for maintaining homeostasis and self-tolerance through their ability to suppress immune responses. For over two decades, Tregs have been the subject of intensive research. The immunosuppressive and migratory potentials of Tregs have been exploited, especially in the areas of cancer, autoimmunity and vaccine development, and many assay protocols have since been developed. However, variations in assay conditions in different studies, as well as covert experimental factors, pose a great challenge to the reproducibility of results. Here, we focus on human Tregs derived from clinical samples and highlighted caveats that should be heeded when conducting Tregs suppression and migration assays. We particularly delineated how factors such as sample processing, choice of reagents and equipment, optimization and other experimental conditions could introduce bias into the assay, and we subsequently proffer recommendations to enhance reliability and reproducibility of results. It is hoped that prioritizing these factors will reduce the tendencies of generating false and misleading results, and thus, help improve our understanding and interpretation of Tregs functional studies.

Matched MeSH terms: T-Lymphocytes, Regulatory
The dichotomy of the systemic and local cytokine responses of mucosal leishmaniasis patients in Sudan: A pilot study

Abdelhaleem AA, Elamin EM, Elhassan AM, Nail AM, Abdullah NE, Mukhtar MM

Trop Biomed, 2020 Dec 01;37(4):877-883.
PMID: 33612741 DOI: 10.47665/tb.37.4.877

Sudanese mucosal leishmaniasis (ML) is a rare clinical form of leishmaniasis and characterized by persistent ulcer of the oral and/or the nasal mucous membranes caused by Leishmania donovani. No data is available about the systemic and local immune responses in mucosal leishmaniasis. This study aimed to measure the systemic and the local cytokines responses of Sudanese ML patients compared to cured cutaneous leishmaniasis patients (Leishmanin skin test positive, LST+ve) and unexposed healthy controls (Leishmanin skin test negative, LST-ve). Six parasitological confirmed ML patients, 7 LST+ve, and 6 LST-ve were enrolled. Systemic Th-1 (IFN-γ and TNF-α), Th-2 (IL-10 and IL-13), Treg (TGF-β1), and inflammatory cytokines IL-6 and IL-8 concentration were measured in the supernatant of whole blood samples following stimulation with live L. donovani promastigotes using ELISA. Local intralesion IL-10, IFN-γ, and IL-13 expression was measured using Real Time PCR. A significant high concentrations of IFN-γ, TNFα, IL-10, TGFβ, IL-6, and IL-8 were detected in the supernatant of stimulated whole blood samples of ML patients compared with the LST+ve and LST-ve controls. Using Real Time-PCR and primers for various cytokines, a significant high expression of TH2 cytokines IL-10 and IL-13 mRNA was detected in contrast to a low TH1 cytokine IFN-γ mRNA in the mucosal lesion. There is a clear dichotomy in the cytokine response during Mucosal leishmaniasis. A significantly high TH1, inflammatory and Treg cytokines response is produced systemically, in contrast to a significant high TH2 cytokines response in the mucosal lesion.

Matched MeSH terms: T-Lymphocytes, Regulatory
Reduced phosphorylated Foxp3 levels in Crimean Congo haemorrhagic fever

Gazi U, Baykam N, Karasartova D, Tosun O, Akdogan O, Yapar D, et al.

Trop Biomed, 2022 Dec 01;39(4):587-591.
PMID: 36602220 DOI: 10.47665/tb.39.4.016

Crimean-Congo haemorrhagic fever (CCHF) is a severe human infection which can lead to fatal consequences. Acute CCHF patients were previously shown to exhibit frequencies of regulatory T-cell (Treg) but lower Treg-mediated suppressive activities than the healthy counterparts. This study aims is to investigate the phosphorylation levels of Foxp3 protein (master regulator of Treg cells) in CCHF patients. Blood samples collected from 18 CCHF patients and nine healthy volunteers were used to isolate peripheral blood mononuclear cells (PBMCs). Total and phosphorylated Foxp3 expression levels in the isolated PBMC samples were monitored by western blot and quantified using ImageJ software. Total Foxp3 expression levels in CCHF patients displayed decreasing trend, but not significantly. In contrast, significantly lower expression levels of phosphorylated Foxp3 were reported in CCHF patients. Our results suggest a possible association between Foxp3 dephosphorylation and CCHF pathogenesis. Nevertheless, more studies are required to evaluate the effect of Foxp3 dephosphorylation on Treg function, which would not only help to enlighten the CCHF pathogenesis but also contribute to the development of effective treatment strategies.

Matched MeSH terms: T-Lymphocytes, Regulatory
CD4+ Foxp3+ Regulatory T-cells in Modulating Inflammatory Microenvironment in Chronic Rhinosinusitis with Nasal Polyps: Progress and Future Prospect

M Yusoff NNF, Ahmad S, Wan Abdul Rahman WF, Mohamud R, C Boer J, Plebanski M, et al.

Cytokine, 2024 Jun;178:156557.
PMID: 38452440 DOI: 10.1016/j.cyto.2024.156557

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of chronic rhinosinusitis (CRS) characterized by the presence of nasal polyps (NP) in the paranasal mucosa. Despite the complex etiology, NP is believed to result from chronic inflammation. The long-term aftermath of the type 2 response is responsible for symptoms seen in NP patients, i.e. rhinorrhea, hyposmia, and nasal obstruction. Immune cellular tolerogenic mechanisms, particularly CD4 + Foxp3 + regulatory T cells (Tregs), are crucial to curtail inflammatory responses. Current evidence suggests impaired Treg activity is the main reason underlying the compromise of self-tolerance, contributing to the onset of CRSwNP. There is compelling evidence that tumor necrosis factor 2 (TNFR2) is preferentially expressed by Tregs, and TNFR2 is able to identify the most potent suppressive subset of Tregs. Tumor necrosis factor (TNF)-TNFR2 interaction plays a decisive role in the activation and expansion of Tregs. This review summarizes current understanding of Tregs biology, focusing on the discussion of the recent advances in the study of TNF-TNFR2 axis in the upregulation of Treg function as a negative feedback mechanism in the control of chronic inflammation. The role of dysregulation of Tregs in the immunopathogenesis of CRSwNP will be analyzed. The future perspective on the harnessing Tregs-mediated self-tolerant mechanism in the management of CRSwNP will be introduced.

Matched MeSH terms: T-Lymphocytes, Regulatory
Fulltext CD4+CD25hiCD127low regulatory T cells are increased in oral squamous cell carcinoma patients

Lim KP, Chun NA, Ismail SM, Abraham MT, Yusoff MN, Zain RB, et al.

PLoS One, 2014;9(8):e103975.
PMID: 25153698 DOI: 10.1371/journal.pone.0103975

Regulatory T cells (Tregs), a subset of CD4+ T cells plays a pivotal role in regulating the immune system. An increase in Treg numbers enables cancer progression by dampening the immune system and allowing tumor cells to evade immune detection and destruction. An increase in Treg numbers and expression of inhibitory cytokines including TGF-β and IL-10 are mechanisms by which Tregs exert their immune suppressive function. However, the presence of Tregs and inhibitory cytokines in oral cancer patients is still unclear. In this study, the presence of circulating Tregs in 39 oral cancer patients and 24 healthy donors was examined by studying the presence of the CD4+CD25hiCD127low cell population in their peripheral blood mononuclear cells using flow cytometry. Serum levels of TGF-β and IL-10 were measured by ELISA. T cell subsets of OSCC patients were found to differ significantly from healthy donors where a decrease in CD8+ cytotoxic T cells and an increase in Tregs (CD4+CD25hiCD127low) were observed. Further, the ratio of CD8+ T cells/Tregs was also decreased in patients compared to healthy donors. The presence of Tregs was accompanied by a decrease in IL-10 but not TGF-β secretion in OSCC patients when compared to donors; in addition, the analysis also revealed that an increased presence of Tregs was accompanied by better patient survival. Amongst OSCC patients, smokers had significantly higher levels of TGF-β. It is apparent that the immune system is compromised in OSCC patients and the characterization of the Treg subpopulation could form a basis for improving our understanding of the perturbations in the immune system that occur during OSCC tumorigenesis.

Matched MeSH terms: T-Lymphocytes, Regulatory/metabolism; T-Lymphocytes, Regulatory/physiology*
Severity of asthma: the role of CD25+, CD30+, NF-kappaB, and apoptotic markers

Abdulamir AS, Kadhim HS, Hafidh RR, Ali MA, Faik I, Abubakar F, et al.

J Investig Allergol Clin Immunol, 2009;19(3):218-24.
PMID: 19610265

OBJECTIVES: We studied the role of the regulatory T cells CD4+CD25+ (Treg) and activated CD4+CD30+ cells in the pathogenesis of asthma and their association with apoptosis and NF-kappaB in patients with mild intermittent asthma (MA), severe persistent asthma (SA), and healthy volunteers (HV).
METHODS: Peripheral blood lymphocytes (PBL) were extracted from asthmatic patients during exacerbations, and CD4+ cells were separated using Dynal beads. Immunostaining of whole PBL for NF-kappaB, Bax, and Bcl-2, and immunostaining of CD4+ cells for CD25+ and CD30+ cells were performed using immunocytochemistry.
RESULTS: Treg cells were expressed at higher levels in MA than in HV and SA (P < .05), while CD30+ T cells were expressed at higher levels in both SA and MA than in HV (P < .05), although there was no remarkable difference between SA and MA (P>.05). Levels of NF-kappaB, Bcl-2, and Bcl-2/Bax increased, whereas those of Bax decreased, progressively, from MA to SA (P < .05). NF-kappaB levels correlated directly with the Bcl-2/Bax ratio and with CD4+CD30+ cells in SA and MA, whereas CD4+CD30+ cells correlated inversely with the Bcl-2/Bax ratio.
CONCLUSIONS: Unregulated Treg cells probably return inflammatory responses to normal values during exacerbations in MA; however, expression of Treg cells was extensively diminished in SA, leading to probable loss of suppressive control over underlying immune reactions. CD4+CD30+ cells were associated with the pathogenesis of asthma but not with severity. NF-kappaB seems to be the central inflammatory factor in SA, with a remarkable loss of PBL apoptosis, diminished Treg levels, and high CD30+ cell levels that probably induce NF-kappaB, which in turn blocks the proapoptotic potential of CD30 induction itself.

Matched MeSH terms: T-Lymphocytes, Regulatory/immunology*; T-Lymphocytes, Regulatory/metabolism
Fulltext Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Hampras SS, Sucheston-Campbell LE, Cannioto R, Chang-Claude J, Modugno F, Dörk T, et al.

Oncotarget, 2016 10 25;7(43):69097-69110.
PMID: 27533245 DOI: 10.18632/oncotarget.10215

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.
METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.
RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).
CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Matched MeSH terms: T-Lymphocytes, Regulatory/immunology; T-Lymphocytes, Regulatory/metabolism
Reduced neonatal regulatory T cell response to microbial stimuli associates with subsequent eczema in high-risk infants

Ismail IH, Boyle RJ, Mah LJ, Licciardi PV, Tang ML

Pediatr Allergy Immunol, 2014 Nov;25(7):674-84.
PMID: 25376403 DOI: 10.1111/pai.12303

Regulatory T cells (Treg) play an essential role in early immune programming and shaping the immune response towards a pro-allergic or tolerant state. We evaluated cord blood Treg and cytokine responses to microbial and non-microbial stimuli in infants at high risk of allergic disease and their associations with development of allergic disease in the first year.

Matched MeSH terms: T-Lymphocytes, Regulatory/immunology*

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