The pathogenic role of stem cell-like memory T cells in rheumatoid arthritis

Abstract Background: Stem cell-like memory T cells (Tscm) are a subset of memory T cells that have the characteristics of stem cells. The role of Tscm cells in rheumatoid arthritis (RA) is not well characterized. Methods: After measuring percentages of CD4+ and CD8+ Tscm cells within the peripheral blood and synovial mononuclear cell populations in RA and health controls (HCs), we confirmed the stem cell nature of Tscm cells from RA patients. The association of Tscm cells with disease activity was also analyzed. Next, the pathogenicity of Tscm cells was examined in RA patients by assessing T cell activation markers and cytokine secretion after stimulation with IL-6 and anti-CD3/CD28 beads. Finally, the transcriptomes of Tscm cells from RA patients were compared with those from HCs. Results: The percentages of CD4+ and CD8+ Tscm cells among total T cells were significantly higher in RA patients than in HCs. Upon stimulation, Tscm cells from RA patients differentiated into daughter T cell subsets with self-renewal capacity. The percentage of CD4+ Tscm cells correlated with expression of RA disease activity markers. Tscm cells from RA patients were more easily activated by IL-6 and anti-CD3/CD28 beads than those from HCs. Transcriptome analysis revealed that Tscm cells from RA patients showed patterns distinct from those of HCs. Conclusion: The percentage of transcriptionally distinct and potentially pathogenic Tscm cells are higher in RA patients than in HCs; these cells may be a continuous source of pathogenic T cells, which perpetuate RA.

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Increased state of activation of CD4 positive T cells and elevated interferon γ production in pouchitis

Gut ◽

10.1136/gut.43.4.499 ◽

1998 ◽

Vol 43 (4) ◽

pp. 499-505 ◽

Cited By ~ 59

Author(s):

A Stallmach ◽

F Schäfer ◽

S Hoffmann ◽

S Weber ◽

I Müller-Molaian ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mononuclear Cells ◽

Interferon Γ ◽

Ileoanal Pouch ◽

T Cell Subsets ◽

Activation Markers ◽

Ifn Γ

Background—Immunoregulatory abnormalities of T cells might be of importance in the pathogenesis of pouchitis after ileoanal pouch anastomosis (IAP).Aims—To characterise T cell subsets, their state of activation, and production of cytokines in inflamed and non-inflamed pouches in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The influence of T cell activation on mucosal transformation was also studied.Patients—Mucosal biopsy specimens were taken from 42 patients with IAP (33 with UC and nine with FAP).Methods—Mononuclear cells were isolated by standard techniques and characterised by three colour flow cytometry. Interferon γ (IFN-γ) production was studied using the ELISPOT technique.Results—In patients with UC with pouchitis there was a significant increase in the CD4:CD8 ratio, expression of activation markers on CD3+ cells, and number of IFNγ producing mononuclear cells compared with patients with UC without pouchitis (CD4:CD8 ratio 1.3 (range 0.7–2.7) versus 0.6 (0.1–1.0), p=0.012). In addition, a positive correlation between increased crypt depth and the number of CD4+ cells (r=0.57) was shown.Conclusion—The observed increase in activated mucosal CD4+ T cells and IFN-γ production might lead to mucosal destruction and crypt hyperplasia as seen in pouchitis.

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CD4+ T-Cell Subsets That Mediate Immunological Memory to Mycobacterium tuberculosis Infection in Mice

Infection and Immunity ◽

10.1128/iai.68.2.621-629.2000 ◽

2000 ◽

Vol 68 (2) ◽

pp. 621-629 ◽

Cited By ~ 75

Author(s):

Peter Andersen ◽

Birgitte Smedegaard

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Immunological Memory ◽

T Cell Subsets ◽

Small Subset ◽

Memory Cells ◽

Activation Markers

ABSTRACT We have studied CD4+ T cells that mediate immunological memory to an intravenous infection with Mycobacterium tuberculosis. The studies were conducted with a mouse model of memory immunity in which mice are rendered immune by a primary infection followed by antibiotic treatment and rest. Shortly after reinfection, tuberculosis-specific memory cells were recruited from the recirculating pool, leading to rapidly increasing precursor frequencies in the liver and a simultaneous decrease in the blood. A small subset of the infiltrating T cells was rapidly activated (<20 h) and expressed high levels of intracellular gamma interferon and the T-cell activation markers CD69 and CD25. These memory effector T cells expressed intermediate levels of CD45RB and were heterogeneous with regard to the L-selectin and CD44 markers. By adoptive transfer into nude mice, the highest level of resistance to a challenge with M. tuberculosis was mediated by CD45RBhigh,l-selectinhigh, CD44low cells. Taken together, these two lines of evidence support an important role for memory cells which have reverted to a naive phenotype in the long-term protection against M. tuberculosis.

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Proteoglycan Aggrecan Conducting T Cell Activation and Apoptosis in a Murine Model of Rheumatoid Arthritis

BioMed Research International ◽

10.1155/2014/942148 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

A. Hanyecz ◽

K. Olasz ◽

O. Tarjanyi ◽

P. Nemeth ◽

K. Mikecz ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Systemic Autoimmune Disease ◽

T Cell Epitopes ◽

T Cell Apoptosis ◽

Autoreactive T Cell

Rheumatoid arthritis (RA) is a systemic autoimmune disease and its targeting of the joints indicates the presence of a candidate autoantigen(s) in synovial joints. Patients with RA show immune responses in their peripheral blood to proteoglycan (PG) aggrecan. One of the most relevant animal models of RA appears to be proteoglycan-induced arthritis (PGIA), and CD4+T cells seem to play a crucial role in the initiation of the disease. In this review, the role of various T cell epitopes of aggrecan in the induction of autoreactive T cell activation and arthritis is discussed. We pay special attention to two critically important arthritogenic epitopes, 5/4E8 and P135H, found in the G1 and G3 domains of PG aggrecan, respectively, in the induction of autoimmune arthritis. Finally, results obtained with the recently developed PG-specific TCR transgenic mice system showed that altered T cell apoptosis, the balance of activation, and apoptosis of autoreactive T cells are critical factors in the development of autoimmunity.

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Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk

Frontiers in Pharmacology ◽

10.3389/fphar.2021.748798 ◽

2021 ◽

Vol 12 ◽

Author(s):

Roberta Kurelic ◽

Paula F. Krieg ◽

Jana K. Sonner ◽

Gloria Bhaiyan ◽

Gustavo C. Ramos ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cross Talk ◽

Cell Activation ◽

Inflammatory Responses ◽

T Cell Subsets ◽

Activation Markers ◽

Tcr Activation ◽

Camp Levels

3′,5′-cyclic adenosine monophosphate (cAMP) is well-known for its diverse immunomodulatory properties, primarily inhibitory effects during T cell activation, proliferation, and production of pro-inflammatory cytokines. A decrease in cAMP levels, due to the hydrolyzing activity of phosphodiesterases (PDE), is favoring inflammatory responses. This can be prevented by selective PDE inhibitors, which makes PDEs important therapeutic targets for autoimmune disorders. In this study, we investigated the specific roles of PDE2A and PDE3B in the regulation of intracellular cAMP levels in different mouse T cell subsets. Unexpectedly, T cell receptor (TCR) activation led to a selective upregulation of PDE2A at the protein level in conventional T cells (Tcon), whereas no changes were detected in regulatory T cells (Treg). In contrast, protein expression of PDE3B was significantly higher in both non-activated and activated Tcon subsets as compared to Treg, with no changes upon TCR engagement. Live-cell imaging of T cells expressing a highly sensitive Förster resonance energy transfer (FRET)-based biosensor, Epac1-camps, has enabled cAMP measurements in real time and revealed stronger responses to the PDE2A inhibitors in activated vs non-activated Tcon. Importantly, stimulation of intracellular cGMP levels with natriuretic peptides led to an increase of cAMP in non-activated and a decrease of cAMP in activated Tcon, suggesting that TCR activation changes the PDE3B-dependent positive to PDE2A-dependent negative cGMP/cAMP cross-talk. Functionally, this switch induced higher expression of early activation markers CD25 and CD69. This constitutes a potentially interesting feed-forward mechanism during autoimmune and inflammatory responses that may be exploited therapeutically.

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AB0151 PRELIMINARY RESULTS SHOW AN INCREASED EXPRESSION OF COINHIBITORY RECEPTORS IN SYSTEMIC SCLEROSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5997 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1376.2-1376

Author(s):

M. Aspari ◽

S. R. Greisen ◽

M. Hvid ◽

B. Deleuran ◽

D. Abraham

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Systemic Sclerosis ◽

T Cell ◽

Healthy Volunteers ◽

T Cell Activation ◽

Cell Activation ◽

Programmed Death ◽

Programmed Death 1

Background:Recent studies suggest dysregulation in T cell activation in systemic sclerosis (SSc). Co-inhibitory-receptors (Co-IRs) such as TIM-3, PD-1 and LAG-3 play a crucial role in controlling excessive T cell activation and in maintaining immune homeostasis. Engagement of these receptors by their ligand’s limits cytokine production in response to TCR or activating NK receptor stimulation and hence limit tissue damage from excessive immune activation. However, chronically increased expression of multiple Co-IRs is a hallmark of immune exhaustion. We evaluate the role of these soluble Co-IRs in diffuse SSc (dcSSc).Objectives:Establish the role of CiR and their ligands in diffuse systemic sclerosis.Understand how immune regulatory mechanisms influence the development of fibrosis.Provide a better understanding of the disease and fibrosis in general.Methods:PBMC’s(Peripheral blood mononuclear cells) and dermal fibroblasts from SSc patients were isolated and investigated for markers of T cell inhibition. These cells were analysed using flow cytometry in a 10 colour panel. Cells were stained for PD1, TIM3, TIGIT, LAG3, CD3, CD8, CD4 and CD19 along with a Live/dead marker. Co-cultures of fibroblasts and PBMCs will be setup, and treated with various drugs that act on the Co-IRs.Results:The proportion of CD4+ T cells expressing PD1 were markedly increased in SSc patients compared to healthy volunteers and Rheumatoid Arthritis patients.There was increased expression of both TIGIT and TIM3 in the CD4+ T cells. (Figure 1)Similarly, the co-expression of these receptors on the CD4+ T cell population was elevated compared to healthy volunteers. (figure 2)Conclusion:Soluble co-inhibitors are differentially expressed in early dcSSc compared to healthy volunteers and other autoimmune diseases. Our preliminary data indicates that these co inhibitors could play an important role in unravelling the pathogenesis of systemic sclerosis. Inhibition or activation of these receptors through different treatment modalities can be utilized as a novel patient centric treatment strategy.References:[1]Fukasawa, T., Yoshizaki, A., Ebata, S., Nakamura, K., Saigusa, R., Miura, S., … Sato, S. (2017). Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis.Arthritis & Rheumatology,69(9), 1879–1890.[2]Greisen S, Rasmussen T, Stengaard-Pedersen K, Hetland M, Hørslev-Petersen K, Hvid M, et al. Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis. Scand J Rheumatol 2014; 43:101-8.[3]de Paoli, F., Nielsen, B., Rasmussen, F., Deleuran, B., & Søndergaard, K. (2014). Abatacept induces clinical improvement in patients with severe systemic sclerosis.Scandinavian Journal of Rheumatology,43(4), 342–345.[4]Kwon, B. (2010). Intervention with costimulatory pathways as a therapeutic approach for graft-versus-host disease.Experimental and Molecular Medicine. Nature Publishing Group.Acknowledgments:FOREUM: Foundation of Research in RheumatologyDisclosure of Interests:None declared

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CVID patients with autoimmunity have elevated T cell expression of granzyme B and HLA-DR and reduced levels of Treg cells

Journal of Clinical Pathology ◽

10.1136/jclinpath-2012-201046 ◽

2012 ◽

Vol 66 (2) ◽

pp. 146-150 ◽

Cited By ~ 25

Author(s):

Clive R D Carter ◽

Ganesha Aravind ◽

Natuley L Smalle ◽

June Y Cole ◽

Sinisa Savic ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Granzyme B ◽

Treg Cells ◽

T Cell Subsets ◽

Activated T Cells ◽

Activation Markers ◽

Hla Dr

AimsCommon variable immunodeficiency (CVID) is a primary antibody immunodeficiency with approximately 20% of patients reporting additional autoimmune symptoms. The primary aim of this study was to compare the levels of activated and regulatory T cells (Treg cells) in CVID patients in an attempt to clarify their possible interactions leading to the generation of autoimmunity.MethodsImmunophenotyping of T cells was performed by flow cytometry using a whole blood approach. Surface expression of human leukocyte antigen HLA class II DR and intracellular levels of granzyme B in T cell subsets were assessed; Treg levels were measured using CD4 CD25, FOXp3 and CTLA-4.ResultsCVID patients had higher levels of granzyme B and HLA-DR on CD8+ T cells compared with control values (mean of 59% vs 30% and 45% vs 21%, respectively). Patients also had reduced levels of Treg cells compared with control values (con mean=3.24% vs pat=2.54%). Patients with autoimmunity (5/23) had a similar level of T cell activation markers to the rest of the patients but with lower Treg cells (mean of 1.1%) and reduced CD25 and CTLA-4 expression. Patients with autoimmunity had a higher ratio of activated to Treg cells compared with patients with no autoimmune symptoms.ConclusionsThese results highlight that reduced levels of Treg cells were associated with elevated levels of activated T cells, suggesting that reduced Treg cells in these patients may have functional consequences in allowing exaggerated T cell responses.

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An imbalance of esophageal effector and regulatory T cell subsets in experimental eosinophilic esophagitis in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00148.2009 ◽

2009 ◽

Vol 297 (3) ◽

pp. G550-G558 ◽

Cited By ~ 22

Author(s):

Xiang Zhu ◽

Meiqin Wang ◽

Caleb H. Crump ◽

Anil Mishra

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Eosinophilic Esophagitis ◽

Critical Role ◽

T Cell Subsets ◽

Activation Markers ◽

Activated T Cell ◽

Anti Inflammatory Cytokine

We recently reported a critical role for T cells in the induction of eosinophilic esophagitis (EE) in mice; however, the role of specific T cell subsets in disease pathogenesis is not yet understood. In the current study, we tested the hypothesis that allergen-induced EE develops in response to the disproportion of functionally different effector and regulatory T cells in the esophagus. Fluorescence-activated cell sorter analysis was performed to examine activated T cell subsets using the cell surface activation markers CD25 and CD69. A significant increase in activated CD4+ and CD4− T cells was observed in the total esophageal cells isolated from the mouse model of EE. Furthermore, an imbalance in the effector and regulatory T cells was observed in the esophagus. The esophageal CD4+CD45RBhigh effector T cells in allergen-challenged mice increased compared with saline-challenged mice (65.4 ± 3.6 × 103 to 44.8 ± 4.2 × 103), whereas CD4+CD45RBlow mostly regulatory T cells decreased in allergen-challenged mice compared with saline-challenged mice (5.8 ± 0.9 × 103 from 10.2 ± 1.7 × 103). The functional characteristics were examined by analysis of the pro- and anti-inflammatory cytokine profile of purified low and high CD4+CD45RB subsets from the spleen. Additionally, a significantly reduced interleukin (IL)-2 production by CD4+CD45RBlow cells in allergen-challenged mice compared with saline-challenged mice was observed. The reduced IL-2 in the CD4+CD45RBlow subset may be associated with reduction of CD4+CD45RBlow subset. In conclusion, our results suggest that local regulatory interaction of CD45RBhigh and CD45RBlow CD4+ T cells may be required for protective and pathogenic immunity in EE.

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Imatinib Mesylate Has a Stage-Specific Inhibitory Role in Generation of CD26highCD8+ Central Memory T Cells in Vitro and in Vivo.

Blood ◽

10.1182/blood.v112.11.3243.3243 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3243-3243

Author(s):

Kazuaki Yokoyama ◽

Tokiko Nagamura-Inoue ◽

Shin Nakayama ◽

Ikuo Ishige ◽

Kazuo Ogami ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Memory T Cells ◽

Central Memory ◽

T Cell Subsets ◽

Effector Memory ◽

Short Term ◽

Central Memory T Cells

Abstract CD26 is a transmembrane glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV) activity as well as costimulatory activity of mitotic signals triggered by the CD3/TCR complex. Based on the expression level of CD26, CD4+ and CD8+ T cells can be divided into 3 (high/intermediate/low or negative) subsets. The significance of CD26 has been studied mainly on CD4+ T cells, and CD26highCD4+ T cells are considered to represent effector memory T cells of a typical Th1 phenotype producing IL2 and IFNg. Furthermore, we reported a significant decrease of this subset in CML patients under imatinib therapy in comparison to those under IFNa therapy and normal volunteers. In contrast, the role of each subset of CD8+ T cells has not yet been clarified. Multi-parameter flow cytometry analysis was performed to characterize CD8+ T cells differentially expressing CD26 in combination with intracellular detection of effector molecules such as perforin (P) and granzyme B (Gr). The capacity to secrete effector cytokines such as IFNg following short-term stimulation was also assessed. As a result, according to the expression level of CD26, we could clearly categorize CD8+ T cells as follows: CD26highCD8+ T cells are defined as central memory T cells which has a phenotype of CD45RO+CD28+CD27+ IFNg+Gr−P+/−, CD26intCD8+ T cells as naïve T cells of CD45ROCD28+ CD27+ IFNg−Gr−P−, and CD26lowCD8+ T cells as effector memory/effector T cells of CD45RO−/+ CD28−CD27−IFNg++Gr++P++, respectively. We next investigated the effects of imatinib on 3 distinct subsets during CD8+ T cell differentiation program. Peripheral blood mononuclear cells were primed with anti-CD3/CD28 MAb and subjected to the grading doses of imatinib for short term culture, followed by flow cytometory. CFSE labeling was used for monitoring cell proliferation. Intriguingly, we found that imatinib dose-dependently inhibits activation, cytokine production and proliferation of CD26highCD8+ central memory T cell subsets in a differentiation stage-specific manner. Finally, we compared the absolute number of peripheral blood CD26highCD8+ T cell subsets between 20 patients with CML in imatinib-induced CCR and 20 normal volunteers, clearly indicating a significant decrease of this subset in CML patients (22.30/ml vs 45.60/ml, p<0.01). The present study offers another evidence for immunomodulatory effects of imatinib or the critical role of Abl (-related) kinase in T cell development, and draws special attention to susceptibility to viral infection of CML patients under long-term imatinib therapy. Figure Figure

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Response to abatacept is associated with the inhibition of proteasome β1i expression in T cells of patients with rheumatoid arthritis

RMD Open ◽

10.1136/rmdopen-2020-001248 ◽

2020 ◽

Vol 6 (3) ◽

pp. e001248

Author(s):

Khetam Ghannam ◽

Lorena Martinez Gamboa ◽

Claudia Kedor ◽

Lydia Spengler ◽

Ulrike Kuckelkorn ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

Disease Activity ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Cell Functions ◽

Induction Of Apoptosis

ObjectiveAbatacept is a biological disease-modifying antirheumatic drug (DMARD) used for the treatment of rheumatoid arthritis (RA) and modulates the costimulatory signal by cluster of differentiation (CD)28:CD80/CD86 interaction required for T cell activation. Since CD28-mediated signalling regulates many T cell functions including cytokine production of, for example, interferons (IFNs), it is of interest to clarify, whether response to abatacept has an effect on the IFN inducible immunoproteasome, as a central regulator of the immune response.MethodsEffects of abatacept on the proteasome were investigated in 39 patients with RA over a period of 24 weeks. Using real-time PCR, transcript levels of constitutive and corresponding immunoproteasome catalytic subunits were investigated at baseline (T0), week 16 (T16) and week 24 (T24) in sorted blood cells. Proteasomal activity and induction of apoptosis after proteasome inhibition were also evaluated.ResultsAbatacept achieved remission or low disease activity in 55% of patients at T16 and in 70% of patients at T24. By two-way analysis of variance (ANOVA), a significant reduction of proteasome immunosubunit β1i was shown only in CD4+ and CD8+ T cells of sustained responders at both T16 and T24. One-way ANOVA analysis for each response group confirmed the results and showed a significant reduction at T24 in CD4+ and CD8+ T cells of the same group. Abatacept did not influence chymotrypsin-like activity of proteasome and had no effect on induction of apoptosis under exposure to a proteasome inhibitor in vitro.ConclusionThe reduction of proteasome immunosubunit β1i in T cells of patients with RA with sustained response to abatacept suggests association of the immunoproteasome of T cells with RA disease activity.

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