AB0084 TNF RECEPTORS PROFILE CHANGES ON CYTOTOXIC T CELLS SUBSETS IN RHEUMATOID ARTHRITIS ARE ASSOCIATED WITH EFFECTIVE TREATMENT

Background:Previous studies of co-expression profile of receptors to tumor necrosis factor alpha (TNF) in rheumatoid arthritis (RA) have revealed a number of indicators associated with diseases activity with 93% sensitivity and 90% specificity. However, the ratio of receptors to cytokines remains poorly understood. However, the question of therapy effect and its effectiveness in various alteration of cytokine receptors balance remains under investigated.Objectives:To evaluate the dynamics of co-expression and quantitative expression of type 1 and 2 receptors for TNF in the subpopulations of CD3+CD8+ cells associated with changes in disease severity before and after effective basic therapy.Methods:Subanalysis of patients with high disease activity level successfully treated with methotrexate and oral glucocorticoids (n = 9) was performed. As a control group, we used data from 43 healthy donors, comparable by sex and age distribution. Subpopulations of cytotoxic T cells were studied, which were included in the final diagnostic models for differentiating different degrees of severity of RA: naive T cells and memory T cells. The dynamics of changes in the indicators of receptors number and proportion of cells expressing the corresponding receptor were compared.Results:For naïve cytotoxic T cells, the main revealed feature was the relative stability of the number of expressed receptors (both TNFR1 and TNFR2), regardless of the therapy, while this number did not significantly differ from healthy ones for TNFR1 and was significantly lower for TNFR2 (p <0.05 for all three fractions). At the same time, in terms of cell percentage, on the contrary, the therapy led to a change in total proportion of TNFR1 + cells closer to healthy donors indicators, and the proportion of TNFR2 + cells in the opposite direction.For cytotoxic T memory cells, it was demonstrated that after successful treatment a significant increase in the number of type 1 receptors was observed, with a decrease in TNFR1+ cells proportion, while these indicators were close to the values of healthy donors. At the same time, healthy donors were characterized by a significantly higher expression of type 2 receptors in terms of cell density of receptors. It is noteworthy that with successful therapy, a slight increase in the number of TNFR2 was observed with a sharp decrease in the proportion of TNFR2+ cells (p = 0.043).Conclusion:The balance of TNF receptor expression on cells actively involved in immunopathological processes affects both the density distribution of receptors on cells and co-expression in a subpopulation. Effective treatment of RA leads to equalization of the expression profile either by the percentage of cells or by the number of receptors, approaching the indicators of healthy donors, but not simultaneously.Disclosure of Interests:None declared

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Co-Expression Profile of TNF Membrane-Bound Receptors Type 1 and 2 in Rheumatoid Arthritis on Immunocompetent Cells Subsets

International Journal of Molecular Sciences ◽

10.3390/ijms21010288 ◽

2019 ◽

Vol 21 (1) ◽

pp. 288

Author(s):

Alina Alshevskaya ◽

Julia Lopatnikova ◽

Julia Zhukova ◽

Oksana Chumasova ◽

Nadezhda Shkaruba ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Disease Activity ◽

Expression Profile ◽

T Helper Cells ◽

Cytotoxic T Cells ◽

T Helper ◽

Healthy Donors ◽

Membrane Bound

Introduction: Tumor necrosis factor (TNFα) is an important proinflammatory cytokine in rheumatoid arthritis (RA) immune processes. However, TNFα activity and functions may be regulated by soluble receptors, which act as decoys, and by number, density, and co-expression of its membrane-bound receptors type 1 and 2 (TNFR1 and TNFR2). The aim of this study was to reveal associations between TNFR1/2 co-expression profile parameters and RA disease activity indicators. Methods: PBMC were analyzed from 46 healthy donors and 64 patients with RA using flow cytometry. Patients were divided according to the disease activity score (DAS) 28 index into groups with high (n = 22, 34.4%), moderate (n = 30, 46.9%), and low (n = 12, 18.8%) disease activity. Co-expression of TNFR1 and TNFR2 was studied by evaluating the percentage of cells, with different receptors, and by counting the number of receptors of each type per cell, using QuantiBritePE beads. Associations between disease severity and activity indicators and parameters of TNFα receptor expression in subpopulations of immune cells were studied. Results: T cell subsets from RA patients were characterized by co-expression of TNFR1 and TNFR2, and were found to differ significantly compared with healthy donors. Memory cells both among T helper cells and cytotoxic T cells demonstrated the most significant differences in TNFR-expression profile. Multivariable logistic regression revealed model to identified RA patients from healthy individual based on the TNFR1/2 co-expression parameters. Conclusion: The profile of TNFR1\2 co-expression differs in RA comparing with health. Proportion of TNFR1+TNFR2- cells increased significantly among memory T helper cells and activated cytotoxic T cells, and decreased significantly among naïve cytotoxic T cells and T regulatory cells as compared with health. The parameters of TNFR1\2 co-expression in RA are associated with clinical and laboratory indicators of disease activity.

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Faculty Opinions recommendation of Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3665956.3386056 ◽

2010 ◽

Author(s):

Florence Apparailly

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Expression Profile ◽

Cd4 T Cells ◽

Microrna Expression ◽

Microrna Expression Profile

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Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro

Life ◽

10.3390/life11030245 ◽

2021 ◽

Vol 11 (3) ◽

pp. 245

Author(s):

Daniil Shevyrev ◽

Valeriy Tereshchenko ◽

Elena Blinova ◽

Nadezda Knauer ◽

Ekaterina Pashkina ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Autoimmune Diseases ◽

Peripheral Blood ◽

Treg Cells ◽

Homeostatic Proliferation ◽

Suppressive Activity ◽

Healthy Donors

Homeostatic proliferation (HP) is a physiological process that reconstitutes the T cell pool after lymphopenia involving Interleukin-7 and 15 (IL-7 and IL-15), which are the key cytokines regulating the process. However, there is no evidence that these cytokines influence the function of regulatory T cells (Tregs). Since lymphopenia often accompanies autoimmune diseases, we decided to study the functional activity of Tregs stimulated by HP cytokines from patients with rheumatoid arthritis as compared with that of those from healthy donors. Since T cell receptor (TCR) signal strength determines the intensity of HP, we imitated slow HP using IL-7 or IL-15 and fast HP using a combination of IL-7 or IL-15 with anti-CD3 antibodies, cultivating Treg cells with peripheral blood mononuclear cells (PBMCs) at a 1:1 ratio. We used peripheral blood from 14 patients with rheumatoid arthritis and 18 healthy volunteers. We also used anti-CD3 and anti-CD3 + IL-2 stimulation as controls. The suppressive activity of Treg cells was evaluated in each case by the inhibition of the proliferation of CD4+ and CD8+ cells. The phenotype and proliferation of purified CD3+CD4+CD25+CD127lo cells were assessed by flow cytometry. The suppressive activity of the total pool of Tregs did not differ between the rheumatoid arthritis and healthy donors; however, it significantly decreased in conditions close to fast HP when the influence of HP cytokines was accompanied by anti-CD3 stimulation. The Treg proliferation caused by HP cytokines was lower in the rheumatoid arthritis (RA) patients than in the healthy individuals. The revealed decrease in Treg suppressive activity could impact the TCR landscape during lymphopenia and lead to the proliferation of potentially self-reactive T cell clones that are able to receive relatively strong TCR signals. This may be another explanation as to why lymphopenia is associated with the development of autoimmune diseases. The revealed decrease in Treg proliferation under IL-7 and IL-15 exposure can lead to a delay in Treg pool reconstitution in patients with rheumatoid arthritis in the case of lymphopenia.

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Cytotoxic T cells isolated from healthy donors and cancer patients kill TGFβ-expressing cancer cells in a TGFβ-dependent manner

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00593-5 ◽

2021 ◽

Author(s):

Morten Orebo Holmström ◽

Rasmus Erik Johansson Mortensen ◽

Angelos Michail Pavlidis ◽

Evelina Martinenaite ◽

Stine Emilie Weis-Banke ◽

...

Keyword(s):

T Cells ◽

Cancer Cells ◽

Cancer Patients ◽

Cytotoxic T Cells ◽

Dependent Manner ◽

Healthy Donors

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Notwithstanding Circumstantial Alibis, Cytotoxic T Cells Can Be Major Killers of HIV-1-Infected Cells

Journal of Virology ◽

10.1128/jvi.00306-16 ◽

2016 ◽

Vol 90 (16) ◽

pp. 7066-7083 ◽

Cited By ~ 14

Author(s):

Saikrishna Gadhamsetty ◽

Tim Coorens ◽

Rob J. de Boer

Keyword(s):

T Cells ◽

Viral Replication ◽

Cytotoxic T Cells ◽

Chronic Phase ◽

Replication Rate ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Eclipse Phase ◽

Hiv 1

ABSTRACTSeveral experiments suggest that in the chronic phase of human immunodeficiency virus type 1 (HIV-1) infection, CD8+cytotoxic T lymphocytes (CTL) contribute very little to the death of productively infected cells. First, the expected life span of productively infected cells is fairly long, i.e., about 1 day. Second, this life span is hardly affected by the depletion of CD8+T cells. Third, the rate at which mutants escaping a CTL response take over the viral population tends to be slow. Our main result is that all these observations are perfectly compatible with killing rates that are much faster than one per day once we invoke the fact that infected cells proceed through an eclipse phase of about 1 day before they start producing virus. Assuming that the major protective effect of CTL is cytolytic, we demonstrate that mathematical models with an eclipse phase account for the data when the killing is fast and when it varies over the life cycle of infected cells. Considering the steady state corresponding to the chronic phase of the infection, we find that the rate of immune escape and the rate at which the viral load increases following CD8+T cell depletion should reflect the viral replication rate, ρ. A meta-analysis of previous data shows that viral replication rates during chronic infection vary between 0.5 ≤ ρ ≤ 1 day−1. Balancing such fast viral replication requires killing rates that are several times larger than ρ, implying that most productively infected cells would die by cytolytic effects.IMPORTANCEMost current data suggest that cytotoxic T cells (CTL) mediate their control of human immunodeficiency virus type 1 (HIV-1) infection by nonlytic mechanisms; i.e., the data suggest that CTL hardly kill. This interpretation of these data has been based upon the general mathematical model for HIV infection. Because this model ignores the eclipse phase between the infection of a target cell and the start of viral production by that cell, we reanalyze the same data sets with novel models that do account for the eclipse phase. We find that the data are perfectly consistent with lytic control by CTL and predict that most productively infected cells are killed by CTL. Because the killing rate should balance the viral replication rate, we estimate both parameters from a large set of published experiments in which CD8+T cells were depleted in simian immunodeficiency virus (SIV)-infected monkeys. This confirms that the killing rate can be much faster than is currently appreciated.

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