scholarly journals Genetic and epigenetic variation in the lineage specification of regulatory T cells

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Aaron Arvey ◽  
Joris van der Veeken ◽  
George Plitas ◽  
Stephen S Rich ◽  
Patrick Concannon ◽  
...  
Keyword(s):  
Treg Cell ◽  
Transcriptional Control ◽  
Cell Function ◽  
Cell Lineage ◽  
Control Program ◽  
Regulatory Elements ◽  
Treg Cells ◽  
Epigenetic Variation ◽  
Nucleotide Polymorphisms ◽  
Lineage Specification

Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification. Analysis of single nucleotide polymorphisms in core lineage-specific enhancers revealed disease associations, which were further corroborated by high-resolution genotyping to fine map causal polymorphisms in lineage-specific enhancers. Our findings suggest that a small set of regulatory elements specify the Treg lineage and that genetic variation in Treg cell-specific enhancers may alter Treg cell function contributing to polygenic disease.

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.

517 Regulatory T cell functional identity is sustained by a glucose:lactate axis that is exploited in the tumor microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A553-A553
Author(s):  
McLane Watson ◽  
Paolo Vignali ◽  
Steven Mullet ◽  
Abigail Overacre-Delgoffe ◽  
Ronal Peralta ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Treg Cell ◽  
High Glucose ◽  
Cell Function ◽  
Treg Cells ◽  
Effector T Cells ◽  
Flux Analysis ◽  
Major Barrier ◽  
Suppressive Function

BackgroundRegulatory T (Treg) cells are vital for preventing autoimmunity but are a major barrier to robust cancer immunity as the tumor microenvironment (TME) recruits and promotes their function. The deregulated cellular metabolism of tumor cells leads to a metabolite-depleted, hypoxic, and acidic TME. While the TME impairs the effector function of highly glycolytic tumor infiltrating CD8 T cells, Treg cell suppressive function is maintained. Further, studies of in vitro induced and ex vivo Treg cells reveal a distinct metabolic profile compared to effector T cells. Thus, it may be that the altered metabolic landscape of the TME and the increased activity of intratumoral Treg cells are linked.MethodsFlow cytometry, isotopic flux analysis, Foxp3 driven Cre-lox, glucose tracers, Seahorse extracellular flux analysis, RNA sequencing.ResultsHere we show Treg cells display heterogeneity in terms of their glucose metabolism and can engage an alternative metabolic pathway to maintain their high suppressive function and proliferation within the TME and other tissues. Tissue derived Treg cells (both at the steady state and under inflammatory conditions) show broad heterogeneity in their ability to take up glucose. However, glucose uptake correlates with poorer suppressive function and long-term functional stability, and culture of Treg cells in high glucose conditions decreased suppressive function. Treg cells under low glucose conditions upregulate genes associated with the uptake and metabolism of the glycolytic end-product lactic acid. Treg cells withstand high lactate conditions, and lactate treatment prevents the destabilizing effects of high glucose culture. Treg cells utilize lactate within the TCA cycle and generate phosphoenolpyruvate (PEP), a critical intermediate that can fuel intratumoral Treg cell proliferation in vivo. Using mice with a Treg cell-restricted deletion of lactate transporter Slc16a1 (MCT1) we show MCT1 is dispensable for peripheral Treg cell function but required intratumorally, resulting in slowed tumor growth and prolonged survival.ConclusionsThese data support a model in which Treg cells are metabolically flexible such that they can utilize ‘alternative’ metabolites present in the TME to maintain their suppressive identity. Further, our studies support the notion that tumors avoid immune destruction not only by depriving effector T cells of essential nutrients, but also by metabolically supporting regulatory T cells.

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.

Combination of Cord Blood T Regulatory Cells with Ruxolitinib Decreases Side Effects and Improves Survival in Xenogenic Graft Vs. Host Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-2
Author(s):  
Ke Zeng ◽  
Meixian Huang ◽  
Li Li ◽  
Mi-Ae Lyu ◽  
Hongbing Ma ◽  
...  
Keyword(s):  
Side Effects ◽  
Cord Blood ◽  
Treg Cell ◽  
Inflammatory Cytokines ◽  
Cell Function ◽  
Treg Cells ◽  
Host Disease ◽  
Suppressor Function ◽  
Cell Suppression ◽  
Suppression Assay

Background: Recent approval of ruxolitinib (rux) for steroid refractory graft versus host disease (GvHD) has revolutionized the field and provided tremendous choice for the patients. However, the side effects including thrombocytopenia leads to dug discontinuation and intolerance. We have previously shown that adoptive therapy with cord blood (CB) derived T regulatory (Treg) cells can prevent and treat GvHD. We hypothesized that the addition of CB Treg therapy to rux based therapy can augment overall efficacy. Methods: CellTrace Violet suppression assay was performed to evaluate the suppressor function of CB Treg cells in the presence or absence of rux. Xenogenic GvHD mouse model was utilized where the NSG mice underwent sublethal irradiation on day -1 followed by injection of 1x107 donor peripheral blood (PB) mononuclear cells (MNCs) on day 0. Oral rux at 1 mg daily was fed continuously to the mice in the presence or absence of 1x107 CB Treg cells, tagged with CellTrace Violet dye, administered on days +4, +7, +11, +18. Mice were followed every other day for weight, GvHD score and survival. Serial blood draws were performed to analyze for cell compartment and cytokine assays. Results: We examine whether the addition of rux impacts the suppressor function of CB Treg cells. Varying concentration of rux including 0.01, 0.05, 0.1 and 0.5 µM were added at 24, 48 and 96 hours of the cell suppression assay. The addition of rux 0.05 µM at 48 hours of the cell suppression culture led to a restoration of poor cell function (Figure A). Lowest GVHD score was reported in the rux+CB Treg combination arms at day +14 when compared to rux alone or CB Treg alone arm which (Figure B) translated into a superior survival in the rux +CB Treg arm (Figure C). Furthermore, an increase in the hemoglobin level (Figure D) and the platelet count (Figure E) was demonstrated in the rux+CB Treg arm. Addition of rux led to longer persistence of the injected CB Treg cells on day 14 (data not shown) which correlated with the increase in the plasma level of the pro-Treg cell signaling markers including IL-7 (Figure F) and IL-15 (Figure G). A decrease in the IL-4 production supported the increased Treg cell function (Figure H). A synergistic suppression of inflammatory cytokines including IL-17 (Figure I) and IL1A (Figure J) was evident in the rux+CB Treg arm. Conclusion: The combination of CB Tregs with ruxolitinib leads to improved overall survival, decreased inflammatory cytokines and improved hematologic parameters. Such combination should be explored in a clinical setting Figure Disclosures Sadeghi: Cellenkos Inc.: Current Employment. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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.

scholarly journals Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle

2021 ◽  
Vol 12 ◽  
Author(s):  
Aikaterini Hatzioannou ◽  
Athina Boumpas ◽  
Miranta Papadopoulou ◽  
Iosif Papafragkos ◽  
Athina Varveri ◽  
...  
Keyword(s):  
Treg Cell ◽  
Therapeutic Potential ◽  
Cell Lineage ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Lessons Learned ◽  
Cell Plasticity ◽  
Therapeutic Implications ◽  
Strategic Role ◽  
Cell Stability

Regulatory T (Treg) cells, possess a strategic role in the maintenance of immune homeostasis, and their function has been closely linked to development of diverse pathologies including autoimmunity and cancer. Comprehensive studies in various disease contexts revealed an increased plasticity as a characteristic of Treg cells. Although Treg cell plasticity comes in various flavors, the major categories enclose the loss of Foxp3 expression, which is the master regulator of Treg cell lineage, giving rise to “ex-Treg” cells and the “fragile” Treg cells in which FOXP3 expression is retained but accompanied by the engagement of an inflammatory program and attenuation of the suppressive activity. Treg cell plasticity possess a tremendous therapeutic potential either by inducing Treg cell de-stabilization to promote anti-tumor immunity, or re-enforcing Treg cell stability to attenuate chronic inflammation. Herein, we review the literature on the Treg cell plasticity with lessons learned in autoimmunity and cancer and discuss challenges and open questions with potential therapeutic implications.

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.

Most human thymic and peripheral-blood CD4+CD25+ regulatory T cells express 2 T-cell receptors

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4063-4070 ◽  
Author(s):  
Heli Tuovinen ◽  
Jukka T. Salminen ◽  
T. Petteri Arstila
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Flow Cytometric Analysis ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Treg Cells ◽  
Allelic Exclusion ◽  
Dual Specificity ◽  
Functional Consequences

Abstract Lack of allelic exclusion in the T-cell receptor (TCR) α locus gives rise to 2 different TCRs in 10% to 30% of all mature T cells, but the significance of such dual specificity remains controversial. Here we show that human CD4+CD25+ regulatory T (Treg) cells express 2 distinct Vα chains and thus 2 TCRs at least 3 times as often as other T cells. Extrapolating from flow cytometric analysis using Vα2-, Vα12-, and Vα24-specific monoclonal antibodies (mAbs), we estimated that between 50% and 99% of the CD25+ Treg cells were dual specific, as compared with about 20% of their CD25– counterparts. Moreover, both TCRs were equally capable of transmitting signals upon ligation. Cells with 2 TCRs also expressed more FOXP3, the Treg-cell lineage specification factor, than cells with a single TCR. Our findings suggest that expression of 2 TCRs favors differentiation to the Treg-cell lineage in humans and raise the question of the potential functional consequences of dual specificity.

scholarly journals Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ricardo A Fernandes ◽  
Chaoran Li ◽  
Gang Wang ◽  
Xinbo Yang ◽  
Christina S Savvides ◽  
...  
Keyword(s):  
Treg Cell ◽  
Cell Biology ◽  
Cell Function ◽  
Cell Clone ◽  
Treg Cells ◽  
Mhc Molecules ◽  
Bona Fide ◽  
Metabolic Indices ◽  
Visceral Adipose

T regulatory (Treg) cells play vital roles in modulating immunity and tissue homeostasis. Their actions depend on TCR recognition of peptide-MHC molecules; yet the degree of peptide specificity of Treg-cell function, and whether Treg ligands can be used to manipulate Treg cell biology are unknown. Here, we developed an Ab-peptide library that enabled unbiased screening of peptides recognized by a bona fide murine Treg cell clone isolated from the visceral adipose tissue (VAT), and identified surrogate agonist peptides, with differing affinities and signaling potencies. The VAT-Treg cells expanded in vivo by one of the surrogate agonists preserved the typical VAT-Treg transcriptional programs. Immunization with this surrogate, especially when coupled with blockade of TNFα signaling, expanded VAT-Treg cells, resulting in protection from inflammation and improved metabolic indices, including promotion of insulin sensitivity. These studies suggest that antigen-specific targeting of VAT-localized Treg cells could eventually be a strategy for improving metabolic disease.

3′-Untranslated regions are important in mRNA localization and translation: lessons from selenium and metallothionein

2004 ◽  
Vol 32 (6) ◽  
pp. 990-993 ◽  
Author(s):  
J. Hesketh
Keyword(s):  
Nuclear Localization ◽  
Transcriptional Control ◽  
Regulatory Elements ◽  
Mrna Localization ◽  
Untranslated Regions ◽  
Physiological Effects ◽  
Nucleotide Polymorphisms ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Control Of Gene Expression

There is increasing evidence that 3′-UTRs (3′-untranslated regions) of mRNAs contain regulatory elements that have important roles in post-transcriptional control of gene expression. For example, 3′-UTRs are important in determining mRNA localization and directing selenocysteine insertion during selenoprotein synthesis. Metallothionein mRNA is localized around the nucleus and associated with the cytoskeleton; this is determined by the 3′-UTR. Deletion and mutagenesis studies are defining the nature of the signal. Incorrect mRNA localization prevents subsequent nuclear localization of metallothionein protein and affects its function. Selenium (Se) is incorporated as selenocysteine into approx. 30 mammalian proteins by a mechanism that requires a specific structure within the 3′-UTR of the corresponding mRNAs. When Se supply is low the effect on selenoprotein expression is not uniform but shows differential effects that are tissue- and protein-specific; there is a ‘prioritization’ of selenoprotein synthesis that is partly influenced by the 3′-UTRs of the different mRNAs. Single-nucleotide polymorphisms in the gene regions corresponding to 3′-UTRs could potentially influence gene regulation. We have discovered a common polymorphism in a part of the glutathione peroxidase 4 gene which corresponds to the 3′-UTR, and our recent results suggest that this single-nucleotide polymorphism has functional and physiological effects, as well as altered frequency in disease.

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