scholarly journals Defective T-Cell Apoptosis and T-Regulatory Cell Dysfunction in Rheumatoid Arthritis

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 223 ◽  
Author(s):  
Charles Malemud
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Clinical Symptoms ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Systemic Autoimmune Disease ◽  
Apoptosis Resistance ◽  
Cell Dysfunction

Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease that mostly affects small and large synovial joints. At the molecular level, RA is characterized by a profoundly defective innate and adaptive immune response that results in a chronic state of inflammation. Two of the most significant alterations in T-lymphocyte (T-cell) dysfunction in RA is the perpetual activation of T-cells that result in an abnormal proliferation state which also stimulate the proliferation of fibroblasts within the joint synovial tissue. This event results in what we have termed “apoptosis resistance”, which we believe is the leading cause of aberrant cell survival in RA. Finding therapies that will induce apoptosis under these conditions is one of the current goals of drug discovery. Over the past several years, a number of T-cell subsets have been identified. One of these T-cell subsets are the T-regulatory (Treg) cells. Under normal conditions Treg cells dictate the state of immune tolerance. However, in RA, the function of Treg cells become compromised resulting in Treg cell dysfunction. It has now been shown that several of the drugs employed in the medical therapy of RA can partially restore Treg cell function, which has also been associated with amelioration of the clinical symptoms of RA.

scholarly journals Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool

2021 ◽  
Author(s):  
Marc Permanyer ◽  
Berislav Bošnjak ◽  
Silke Glage ◽  
Michaela Friedrichsen ◽  
Stefan Floess ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Interleukin 2 ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Receptor Expression ◽  
Spontaneous Mutant ◽  
Cell Pool ◽  
And Function

AbstractSignaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.

scholarly journals DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions

2021 ◽  
Vol 118 (21) ◽  
pp. e2021309118
Author(s):  
Kazuki Sato ◽  
Yumi Yamashita-Kanemaru ◽  
Fumie Abe ◽  
Rikito Murata ◽  
Yuho Nakamura-Shinya ◽  
...  
Keyword(s):  
Treg Cell ◽  
Intracellular Signaling ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Mammalian Target Of Rapamycin ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Cell Dysfunction ◽  
Inflammatory Conditions ◽  
Treg Cell Function

Regulatory T (Treg) cells that express forkhead box P3 (Foxp3) are pivotal for immune tolerance. Although inflammatory mediators cause Foxp3 instability and Treg cell dysfunction, their regulatory mechanisms remain incompletely understood. Here, we show that the transfer of Treg cells deficient in the activating immunoreceptor DNAM-1 ameliorated the development of graft-versus-host disease better than did wild-type Treg cells. We found that DNAM-1 competes with T cell immunoreceptor with Ig and ITIM domains (TIGIT) in binding to their common ligand CD155 and therefore regulates TIGIT signaling to down-regulate Treg cell function without DNAM-1–mediated intracellular signaling. DNAM-1 deficiency augments TIGIT signaling; this subsequently inhibits activation of the protein kinase B–mammalian target of rapamycin complex 1 pathway, resulting in the maintenance of Foxp3 expression and Treg cell function under inflammatory conditions. These findings demonstrate that DNAM-1 regulates Treg cell function via TIGIT signaling and thus, it is a potential molecular target for augmenting Treg function in inflammatory diseases.

scholarly journals TCR repertoire analysis reveals effector memory T cells differentiation into Th17 cells in rheumatoid arthritis

2019 ◽  
Author(s):  
Xu Jiang ◽  
Shi-yu Wang ◽  
Chen Zhou ◽  
Jing-hua Wu ◽  
Yu-hao Jiao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Th17 Cells ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Systemic Autoimmune Disease ◽  
Autoreactive T Cell

AbstractThe pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells, with highly similar TCR repertoires between them. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Moreover, TCR diversity in subsets including Th17 was negatively correlated with RA disease activity indices such as C-reactive protein and erythrocyte sedimentation rate. Thus, shared and abnormally expanded EMT and Th17 TCR repertoires might be pivotal for RA pathogenesis.

scholarly journals Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

2021 ◽  
Author(s):  
Khalid W Kalim ◽  
Jun-Qi Yang ◽  
Mark Wunderlich ◽  
Vishnu Modur ◽  
Phuong Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Plasticity ◽  
Effector T Cell ◽  
Cell Immunity

Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T cell function. In the tumor microenvironment, Treg cells are utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes anti-tumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.

Role of regulatory T-cells in autoimmunity

2009 ◽  
Vol 116 (8) ◽  
pp. 639-649 ◽  
Author(s):  
Richard J. Mellanby ◽  
David C. Thomas ◽  
Jonathan Lamb
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Cell Function ◽  
Cell Subset ◽  
Treg Cells ◽  
Self Tolerance

There has been considerable historical interest in the concept of a specialist T-cell subset which suppresses over-zealous or inappropriate T-cell responses. However, it was not until the discovery that CD4+CD25+ T-cells had suppressive capabilities both in vitro and in vivo that this concept regained credibility and developed into one of the most active research areas in immunology today. The notion that in healthy individuals there is a subset of Treg-cells (regulatory T-cells) involved in ‘policing’ the immune system has led to the intensive exploration of the role of this subset in disease resulting in a number of studies concluding that a quantitative or qualitative decline in Treg-cells is an important part of the breakdown in self-tolerance leading to the development of autoimmune diseases. Although Treg-cells have subsequently been widely postulated to represent a potential immunotherapy option for patients with autoimmune disease, several studies of autoimmune disorders have demonstrated high numbers of Treg-cells in inflamed tissue. The present review highlights the need to consider a range of other factors which may be impairing Treg-cell function when considering the mechanisms involved in the breakdown of self-tolerance rather than focussing on intrinsic Treg-cell factors.

scholarly journals B cells are required for induction of T cell abnormalities in a murine retrovirus-induced immunodeficiency syndrome.

1990 ◽  
Vol 171 (1) ◽  
pp. 315-320 ◽  
Author(s):  
A Cerny ◽  
A W Hügin ◽  
R R Hardy ◽  
K Hayakawa ◽  
R M Zinkernagel ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Cell Function ◽  
T Cell Subsets ◽  
Mu Suppression ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
Virus Expression ◽  
High Level ◽  
Immunodeficiency Syndrome

The role of B cells in induction of phenotypic and functional abnormalities of T cells in a murine retrovirus-induced immunodeficiency syndrome, MAIDS, was evaluated in mice depleted of mature B cells from birth with anti-IgM antibodies (mu-suppressed) and infected at 4 wk of age. Multicolor FACS analyses of CD4+ T cell subsets showed that development of phenotypic abnormalities of these cells at 9 wk after infection was completely inhibited by mu-suppression. Furthermore, induction of impaired proliferative responses to Con A and alloantigens and CTL responses to alloantigens was fully blocked in antibody-treated animals. The extent of virus replication was comparable in spleens of untreated and mu-suppressed mice. Retroviral induction of T cell dysfunction in MAIDS is thus dependent on the presence of B cells, and high level virus expression in mice without B cells has little or no effect on T cell function.

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

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.

Myeloma Microenvironment Controls T Regulatory Cell Activity: Potential Target for Therapeutic Interventions.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 659-659
Author(s):  
Rao H. Prabhala ◽  
Paola Neri ◽  
Mariateresa Fulciniti ◽  
Vanessa A. Therrien ◽  
Vidit Munshi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Treg Cell ◽  
Treg Cells ◽  
Cell Number ◽  
T Cell Proliferation ◽  
Normal Donor ◽  
Suppressive Activity ◽  
Cell Dysfunction ◽  
And Function

Abstract Multiple myeloma (MM) is associated with significant immune dysfunction. The biological basis of this dysfunction remains ill defined. We have previously observed significantly decreased number of T regulatory (Treg) cells, as measured by Foxp3 expression, in both MGUS and MM compared to normal donors. Moreover, Treg cells in MM and MGUS are unable to suppress anti-CD3-mediated T cell proliferation. Here, we have further analyzed elements of bone marrow (BM) microenvironment that may be responsible for dysfunctional Treg cells in MM. Both cellular and soluble components of the BM microenvironment directly, by cell-cell interactions, as well as by production of soluble factors not only affect MM cell growth, survival, migration and drug resistance but also modulate function of immune components. Interactions between MM cells and bone marrow stromal cells trigger production of IL-6, as well as a number of other cytokines and chemokines including TNF-α , VGEF, IGF-1, SDF-1α , IL-1β , TGF-β , and MIP-1α /β with immunomodulatory activity. We and others have in fact demonstrated significantly elevated levels of serum IL-6 as well as soluble IL-6 (sIL-6) receptor in MM. Based on in vivo data that IL-6 can modulate Treg cell number and function in a murine model of asthma, we evaluated its role in Treg cell dysfunction in myeloma. We performed T cell proliferation assays with soluble anti-CD3 antibody with or without Treg cells from normal donors in presence or absence of IL-6/sIL-6R. We observed that the presence of IL-6 and/or sIL-6 receptor leads to loss of normal Treg cell suppressive activity on normal donor T cells (from inhibition of proliferation by 27% to increase in proliferation by 6% in presence of IL-6/sIL-6R, p=0.01). The Treg cell dysfunction observed here is similar to that observed in MM patients. Conversely, when Treg cells from MM patients were treated with IL-6 receptor super antagonist, Sant 7, prior to their addition to T cell proliferation assay, the suppressive activity of Treg cells was restored. Presence of untreated Treg cells was associated with 28% increase in T cell proliferation while Sant 7-treated Treg cells led to 35% inhibition of T cell proliferation (p=0.01). Additionally, we observed expansion of Foxp3+ Treg cell number in PBMC from MM patients following in vitro treatment with anti-IL-6 antibody. Furthermore, TGF-β , a known stimulator of Treg cell function was less effective in stimulating FOXP3+ Treg cells in PBMCs from MM patients (15.2%) compared to normal donor PBMCs (24%). Since Treg cells require interaction with antigen presenting cells (APC), we evaluated effects of IL-6 and TGF-β on the ability of APC to help suppressive activity of Treg cells. Prior exposure of mature dendritic cells to IL-6 and TGF-β abrogated Treg cell suppressive activity from 47% inhibition to 23% increase in T cell proliferation (p=0.01). In conclusion, we have observed that combination of IL6/sIL6R and TGF-β significantly affects Treg cell number and function. These cytokines are significantly expressed in the MM BM microenvironment and may be responsible for the observed Treg cell dysfunction. These cytokines thus may be targets to modulate immune responses in myeloma to enhance immune function and devise effective vaccination strategies in the future.

scholarly journals PD-1 overexpression determines the disproportion of circulating Th1/Th17/Treg cells and clinical outcome of multiple myeloma

2019 ◽  
Author(s):  
Agata Kosmaczewska ◽  
Anna Masternak ◽  
Katarzyna Kosciow ◽  
Lidia Ciszak ◽  
Lidia Usnarska-Zubkiewicz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Treg Cell ◽  
Immune Checkpoint ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Immune Checkpoints ◽  
Systemic Immunosuppression

Abstract Background The role of particular immune checkpoints in the induction of systemic immunosuppression, which severely complicates the clinical course and prognosis in multiple myeloma (MM), is still unresolved. Only a subset of MM patients treated with checkpoint inhibitors derive benefits, suggesting differential participation of relevant receptors in the inhibitory signaling pathway. This study was undertaken to identify an immune checkpoint playing a key role in systemic T-cell-related immune deficiency in MM in the context of Th1/Th17/Treg cell distribution.Methods We used flow cytometry assay to examine the expression of PD-1, BTLA, and CTLA-4 in peripheral blood (PB) CD4 + , CD4 + CD127 + (Teff), and CD4 + CD127 - (Treg) T cell subsets as well as the balance of Th1/Th17/Treg cells. The study group consisted of 40 untreated (newly diagnosed or relapsed/refractory) myeloma patients in different clinical stages. The obtained results were compared to those observed in 20 healthy controls.Results Among immune checkpoints studied, only PD-1 was expressed on a significantly increased proportion of circulating Teff and Treg cells in MM; we also noted a positive correlation of PD-1 expression with clinical stage. Furthermore, the percentage of PD-1 + Teff cells was correlated with beta2-microglobulin serum concentration and shorter overall survival (OS). We also found higher Th17 and Treg compartments in PB irrespectively of tumor stage; however, in some studied subsets, a decrease at stage III was observed. Moreover, PB Th1 deficit (more pronounced in advanced disease) was also observed. Except for the PD-1 + Teff subset, none of the examined cell population was related to OS.Conclusions The study indicates that PD-1 expression on circulating T cell subsets may contribute to the imbalance in PB Th1/Th17/Treg cell distribution and systemic immunosuppression in MM. PD-1 seems to be the only immune checkpoint determining clinical behavior of patients, thereby strengthening the therapeutic potential for inhibitors.

Dysfunctional T Regulatory Cells in Myeloma: Molecular Mechanisms of Dysregulation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3462-3462
Author(s):  
Rao H. Prabhala ◽  
Paola Neri ◽  
Pierfrancesco Tassone ◽  
Jooeun E. Bae ◽  
Masood A. Shammas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Cell Activity ◽  
T Cell Responses ◽  
Treg Cells ◽  
Cell Responses ◽  
Treg Cell Function

Abstract Multiple myeloma (MM) is characterized by production of monoclonal immunoglobulin, associated with suppressed uninvolved immunoglobulins and dysfunctional T cell responses. The biological basis of this dysfunction remains ill defined. Since T regulatory (Treg) cells play an important role in suppressing normal immune responses, we have here evaluated the potential role of Treg cells in immune dysfunction in MM. We observed a significant increase in CD4+CD25+ T cells in individuals with monoclonal gammopathy of undetermined significance (MGUS) and patients with MM compared to normal donors (25% and 26% versus 14%, respectively); however, Treg cells as measured by Foxp3 expression are significantly decreased in both MGUS (1.6±0.5%, p&lt;0.01) and MM (1.6±0.5%, p&lt;0.01) compared to normal donors (6.0±0.8%). Additionally, these Treg cells also do not function normally. Treg cells from patients with MM and MGUS even when added in higher proportions are unable to suppress anti-CD3-mediated T cell proliferation. This decreased number and function of Treg cells in MGUS and in MM may account, at least in part, for the non-specific increase in CD4+CD25+ T cells, thereby contributing to dysfunctional T cell responses. We have further analyzed the molecular basis for the Treg cell dysfunction in myeloma. Based on the preliminary results suggesting a role of IL-6 in Treg cell function and since both serum IL-6 and soluble IL-6 receptor levels are significantly elevated in MGUS and MM, we evaluated the role of IL-6 and its soluble receptor on Treg cell function. We observed that the addition of IL-6 and/or sIL-6 receptor to the culture leads to loss of Treg cell activity in normal donor cells similar to one observed in myeloma patients; and conversely, when Treg cells from MM patients are treated with the anti-IL-6 antibody or IL-6 receptor super antagonist, sant 7, the suppressive activity of Treg cells is restored. Additionally, we have preliminary evidence of expansion of Foxp3+ cell numbers in PBMC from MM patients following in vitro treatment with anti-IL-6 antibody. This data suggests a role of IL-6 and bone marrow microenvironment in dysfunctional Treg cells in MM and that inhibition of IL-6 signaling results in beneficial effects on T cell activity by increasing Treg cell activity. A blockade of IL-6 signaling thus emerges as a potential approach to establish immune homeostasis to improve immune function in MM.

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