The Interplay Between Monocytes/Macrophages and CD4+ T Cell Subsets in Rheumatoid Arthritis

ObjectivesThis study investigates pathogenic and protective polyfunctional T-cell responses in patient with rheumatoid arthritis (RA), individuals at risk (IAR) and healthy control (HC) synovial-tissue biopsies and identifies the presence of a novel population of pathogenic polyfunctional T-cells that are enriched in the RA joint prior to the development of clinical inflammation.MethodsPathway enrichment analysis of previously obtained RNAseq data of synovial biopsies from RA (n=118), IAR (n=20) and HC (n=44) was performed. Single-cell synovial tissue suspensions from RA (n=10), IAR (n=7) and HC (n=7) and paired peripheral blood mononuclear cells (PBMC) were stimulated in vitro and polyfunctional synovial T-cell subsets examined by flow cytometric analysis, simplified presentation of incredibly complex evaluations (SPICE) and FlowSom clustering. Flow-imaging was utilised to confirm specific T-cell cluster identification. Fluorescent lifetime imaging microscopy (FLIM) was used to visualise metabolic status of sorted T-cell populations.ResultsIncreased plasticity of Tfh cells and CD4 T-cell polyfunctionality with enriched memory Treg cell responses was demonstrated in RA patient synovial tissue. Synovial-tissue RNAseq analysis reveals that enrichment in T-cell activation and differentiation pathways pre-dates the onset of RA. Switch from potentially protective IL-4 and granulocyte macrophage colony stimulating factor (GMCSF) dominated polyfunctional CD4 T-cell responses towards pathogenic polyfunctionality is evident in patient with IAR and RA synovial tissue. Cluster analysis reveals the accumulation of highly polyfunctional CD4+ CD8dim T-cells in IAR and RA but not HC synovial tissue. CD4+ CD8dim T-cells show increased utilisation of oxidative phosphorylation, a characteristic of metabolically primed memory T-cells. Frequency of synovial CD4+ CD8dim T-cells correlates with RA disease activity.ConclusionSwitch from potentially protective to pathogenic T-cell polyfunctionality pre-dates the onset of clinical inflammation and constitutes an opportunity for therapeutic intervention in RA.

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Cell Surface CD28 Levels Define Four CD4+ T Cell Subsets: Abnormal Expression in Rheumatoid Arthritis

Clinical Immunology ◽

10.1006/clim.2001.5003 ◽

2001 ◽

Vol 99 (2) ◽

pp. 253-265 ◽

Cited By ~ 26

Author(s):

Laura-Inés Salazar-Fontana ◽

Eva Sanz ◽

Isabel Mérida ◽

Antonio Zea ◽

Ana Sanchez-Atrio ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

Cell Surface ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Abnormal Expression

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Comprehensive TCR repertoire analysis of CD4+ T-cell subsets in rheumatoid arthritis

Journal of Autoimmunity ◽

10.1016/j.jaut.2020.102432 ◽

2020 ◽

Vol 109 ◽

pp. 102432 ◽

Cited By ~ 2

Author(s):

Xu Jiang ◽

Shiyu Wang ◽

Chen Zhou ◽

Jinghua Wu ◽

Yuhao Jiao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Repertoire Analysis ◽

Tcr Repertoire

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Reduction of peripheral regulatory T cells in active rheumatoid arthritis patients with coronary artery disease

BMC Immunology ◽

10.1186/s12865-021-00466-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yanyan Wang ◽

Rui Su ◽

Baochen Li ◽

Qiaoling Guo ◽

Fangyuan Hu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

Active Rheumatoid Arthritis ◽

Absolute Number ◽

Treg Cells ◽

T Cell Subsets ◽

Cd4 T Cell ◽

The Absolute ◽

Artery Disease

Abstract Objective To identify lymphocyte and CD4 + T cell subset characteristics, particularly regulatory T cells (Tregs), in active rheumatoid arthritis (RA) patients with coronary artery disease (CAD). Methods A total of 54 RA patients with CAD (RA-CAD group), 43 RA patients without CAD (pure RA group), and 43 healthy controls (HC group) were enrolled. The absolute number and frequency of lymphocyte subpopulations and CD4 + T cell subsets were analyzed by flow cytometry. Serum levels of cytokines were analyzed using a cytometric bead array. Clinical and laboratory data were collected retrospectively and their correlation with CD4 + T subsets were analyzed. Results There was a significant decrease in the absolute number of Treg cells (CD4 + CD25 + Foxp3 + T cells) in the RA-CAD group compared to the pure RA group (p < 0.001). Similarly, both the absolute number (p = 0.001) and frequency (p = 0.011) of Tregs in the RA-CAD group were decreased compared to the HCs, causing a Th17/Treg imbalance (p = 0.044). No difference was found in the absolute number and frequency of Treg cells between the pure RA and HC groups. However, the absolute Th17 cell count was increased in the pure RA group (p = 0.032). The serum level of cytokine IL-17 was lower in the RA-CAD group than in the pure RA group (p = 0.023). In the RA-CAD group, the Treg number was negatively correlated with the RA disease activity score and ESR value, and LDL and ApoB100 levels were negatively correlated with the number of Th17 cells. Conclusions Active RA patients with CAD sustain more severe immune tolerance damage and Th17/Treg disorder. Monitoring of lymphocyte and CD4 + T cell subsets, particularly Treg cells, is crucial to understanding immune status in this group. Focusing on RA activity and CAD risk control, immune-regulatory therapy based on the Treg level may be more beneficial for RA patients with CAD.

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CD4+T-cell subsets in rheumatoid arthritis

International Journal of Clinical Rheumatology ◽

10.2217/ijr.11.69 ◽

2012 ◽

Vol 7 (1) ◽

pp. 37-53 ◽

Cited By ~ 4

Author(s):

Frederique Ponchel ◽

Edward Vital ◽

Sarah R Kingsbury ◽

Yasser M El-Sherbiny

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

T Cell Subsets ◽

Cd4 T Cell

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Functional CD4 T cell subsets activity in C57BL/10 mice with inherited low IgG responsiveness

Immunology Letters ◽

10.1016/s0165-2478(97)87728-0 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 223

Author(s):

B RÃhovÃ¡

Keyword(s):

T Cell ◽

T Cell Subsets ◽

Cd4 T Cell

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Faculty Opinions recommendation of Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets.

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

10.3410/f.10688957.793531683 ◽

2017 ◽

Author(s):

Luisa Figueiredo

Keyword(s):

T Cell ◽

Cutting Edge ◽

T Cell Subsets ◽

Cd4 T Cell

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Traditional Thai Massage Promoted Immunity in the Elderly via Attenuation of Senescent CD4+ T Cell Subsets: A Randomized Crossover Study

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18063210 ◽

2021 ◽

Vol 18 (6) ◽

pp. 3210

Author(s):

Kanda Sornkayasit ◽

Amonrat Jumnainsong ◽

Wisitsak Phoksawat ◽

Wichai Eungpinichpong ◽

Chanvit Leelayuwat

Keyword(s):

T Cells ◽

T Cell ◽

Crossover Study ◽

Intracellular Cytokine Staining ◽

The Elderly ◽

Complementary Therapy ◽

T Cell Subsets ◽

Cd4 T Cell ◽

T Subsets ◽

Randomized Crossover Study

The beneficial physiological effects of traditional Thai massage (TTM) have been previously documented. However, its effect on immune status, particularly in the elderly, has not been explored. This study aimed to investigate the effects of multiple rounds of TTM on senescent CD4+ T cell subsets in the elderly. The study recruited 12 volunteers (61–75 years), with senescent CD4+ T cell subsets, who received six weekly 1-h TTM sessions or rest, using a randomized controlled crossover study with a 30-day washout period. Flow cytometry analysis of surface markers and intracellular cytokine staining was performed. TTM could attenuate the senescent CD4+ T cell subsets, especially in CD4+28null NKG2D+ T cells (n = 12; p < 0.001). The participants were allocated into two groups (low < 2.75% or high ≥ 2.75%) depending on the number of CD4+28null NKG2D+ T cells. After receiving TTM over 6 sessions, the cell population of the high group had significantly decreased (p < 0.001), but the low group had no significant changes. In conclusion, multiple rounds of TTM may promote immunity through the attenuation of aberrant CD4+ T subsets. TTM may be provided as a complementary therapy to improve the immune system in elderly populations.

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Differential polarization and activation dynamics of systemic T helper cell subsets after aneurysmal subarachnoid hemorrhage (SAH) and during post-SAH complications

Scientific Reports ◽

10.1038/s41598-021-92873-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shafqat Rasul Chaudhry ◽

Ulf Dietrich Kahlert ◽

Thomas Mehari Kinfe ◽

Elmar Endl ◽

Andreas Dolf ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

T Cell ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

T Cell Subsets ◽

Cd4 T Cell ◽

T Helper ◽

Activation Markers ◽

Hla Dr

AbstractAneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Devastating post-SAH complications, such as cerebral vasospasm (CVS), delayed cerebral ischemia or seizures to mention a few, are mainly responsible for the poor clinical outcome. Inflammation plays an indispensable role during early brain injury (EBI) and delayed brain injury (DBI) phases over which these complications arise. T helper cells are the major cytokine secreting cells of adaptive immunity that can polarize to multiple functionally unique sub-populations. Here, we investigate different CD4+ T cell subsets during EBI and DBI phases after SAH, and their dynamics during post-SAH complications. Peripheral venous blood from 15 SAH patients during EBI and DBI phases, was analyzed by multicolour flowcytometry. Different subsets of CD3+ CD4+ T cells were characterized by differential cell surface expression of CXCR3 and CCR6 into Th1, Th2, Th17, whereas Tregs were defined by CD25hiCD127lo. The analysis of activation states was done by the expression of stable activation markers CD38 and HLA-DR. Interestingly, compared to healthy controls, Tregs were significantly increased during both EBI and DBI phases. Different activation states of Tregs showed differential significant increase during EBI and DBI phases compared to controls. HLA-DR− CD38+ Tregs were significantly increased during DBI phase compared to EBI phase in SAH patients developing CVS, seizures and infections. However, HLA-DR− CD38− Tregs were significantly reduced during EBI phase in patients with cerebral ischemia (CI) compared to those without CI. HLA-DR− CD38− Th2 cells were significantly increased during EBI phase compared to controls. A significant reduction in Th17/Tregs and HLA-DR− CD38+ Th17/Tregs ratios was observed during both EBI and DBI phases compared to controls. While HLA-DR− CD38− Th17/Tregs and HLA-DR− CD38− Th1/Th2 ratios were impaired only during EBI phase compared to controls. In conclusion, CD4+ T cell subsets display dynamic and unique activation patterns after SAH and during the course of the manifestation of post-SAH complications, which may be helpful for the development of precision neurovascular care. However, to claim this, confirmatory studies with larger patient cohorts, ideally from different ethnic backgrounds, are required. Moreover, our descriptive study may be the grounds for subsequent lab endeavors to explore the underlying mechanisms of our observations.

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