Collagen II-primed Foxp3 Transduced T Cells Ameliorate Collagen-induced Arthritis in Rats: The Effect of Antigenic Priming on T Regulatory Cell Function

Regulatory T cells (Tregs) play a major role in the prevention of autoimmune diseases. Transfer of Foxp3 gene into conventional T cells converts their phenotype to regulatory T cells. Therefore, the question arises as to whether adoptively transferred in vitro differentiated Treg cells specific for a locally expressed antigen might have better inhibitory effects on the progression of the disease as compared with antigen-nonspecific T reg cells. Herein, we investigated the therapeutic potential of primed and unprimed retrovirus mediated Foxp3-overexpression T cells following intravenously injected of these cells into affected rats with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. Our analyses demonstrate that systemic administration of collagen II primed Foxp3-transduced T cells could markedly ameliorate CIA inflammatory responses at clinical (p<0.0014) and pathological exchanges including cellular infiltration (p=0.002), bone erosion (p=0.0013) and synovial hyperplasia (p=0.002). In contrast, collagen II unprimed Foxp3-transduced T cells like as collagen II primed or unprimed GFP-transduced T cells did not reveal any beneficial effects on arthritis features as compared with untreated group (p>0.05). Therefore, we believe that collagen II primed Foxp3-transduced T cells are interacting locally and systemically with immune cells which reveled with decreasing of T cells infiltration into joints along with specific CII IgG production. Considering the results described here, it appears that the using patients' T cells which previously exposed to specific antigens may have more effective therapeutic advantage in the production of induced regulatory T cells in the treatment of arthritis.

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Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms23020732 ◽

2022 ◽

Vol 23 (2) ◽

pp. 732

Author(s):

Katrin Peckert-Maier ◽

Dmytro Royzman ◽

Pia Langguth ◽

Anita Marosan ◽

Astrid Strack ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Transplant Rejection ◽

Immune Checkpoints ◽

Potential Candidate ◽

Resolution Of Inflammation ◽

Checkpoint Molecule

Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4+ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.

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Characterizing T Cells in SCID Patients Presenting with Reactive or Residual T Lymphocytes

Clinical and Developmental Immunology ◽

10.1155/2012/261470 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Atar Lev ◽

Amos J. Simon ◽

Luba Trakhtenbrot ◽

Itamar Goldstein ◽

Meital Nagar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cell Function ◽

Severe Combined Immunodeficiency ◽

Cell Activity ◽

Mhc Ii ◽

Cell Functions ◽

Circulating T Cells

Introduction. Patients with severe combined immunodeficiency (SCID) may present with residual circulating T cells. While all cells are functionally deficient, resulting in high susceptibility to infections, only some of these cells are causing autoimmune symptoms.Methods. Here we compared T-cell functions including the number of circulating CD3+T cells,in vitroresponses to mitogens, T-cell receptor (TCR) repertoire, TCR excision circles (TREC) levels, and regulatory T cells (Tregs) enumeration in several immunodeficinecy subtypes, clinically presenting with nonreactive residual cells (MHC-II deficiency) or reactive cells. The latter includes patients with autoreactive clonal expanded T cell and patients with alloreactive transplacentally maternal T cells.Results. MHC-II deficient patients had slightly reduced T-cell function, normal TRECs, TCR repertoires, and normal Tregs enumeration. In contrast, patients with reactive T cells exhibited poor T-cell differentiation and activity. While the autoreactive cells displayed significantly reduced Tregs numbers, the alloreactive transplacentally acquired maternal lymphocytes had high functional Tregs.Conclusion. SCID patients presenting with circulating T cells show different patterns of T-cell activity and regulatory T cells enumeration that dictates the immunodeficient and autoimmune manifestations. We suggest that a high-tolerance capacity of the alloreactive transplacentally acquired maternal lymphocytes represents a toleration advantage, yet still associated with severe immunodeficiency.

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Inhibition of two-pore channels in antigen-presenting cells promotes the expansion of TNFR2-expressing CD4+Foxp3+ regulatory T cells

Science Advances ◽

10.1126/sciadv.aba6584 ◽

2020 ◽

Vol 6 (40) ◽

pp. eaba6584

Author(s):

Tianzhen He ◽

De Yang ◽

Xiao-Qing Li ◽

Mengmeng Jiang ◽

Md Sahidul Islam ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Antigen Presenting Cells ◽

Surface Expression ◽

Pore Channel ◽

Dependent Manner ◽

Antigen Presenting

CD4+Foxp3+ regulatory T cells (Tregs) are pivotal for the inhibition of autoimmune inflammatory responses. One way to therapeutically harness the immunosuppressive actions of Tregs is to stimulate the proliferative expansion of TNFR2-expressing CD4+Foxp3+ Tregs via transmembrane TNF (tmTNF). Here, we report that two-pore channel (TPC) inhibitors markedly enhance tmTNF expression on antigen-presenting cells. Furthermore, injection of TPC inhibitors including tetrandrine, or TPC-specific siRNAs in mice, increases the number of Tregs in a tmTNF/TNFR2-dependent manner. In a mouse colitis model, inhibition of TPCs by tetrandrine markedly attenuates colon inflammation by expansion of Tregs. Mechanistically, we show that TPC inhibitors enhance tmTNF levels by disrupting surface expression of TNF-α–converting enzyme by regulating vesicle trafficking. These results suggest that the therapeutic potential of TPC inhibitors is mediated by expansion of TNFR2-expressing Tregs and elucidate the basis of clinical use in the treatment of autoimmune and other inflammatory diseases.

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Induction of CD4+CD25+ Regulatory T Cells from In Vitro Grown Human Mononuclear Cells by Sparteine Sulfate and Harpagoside

Biology ◽

10.3390/biology9080211 ◽

2020 ◽

Vol 9 (8) ◽

pp. 211 ◽

Cited By ~ 1

Author(s):

Nour Z. Atwany ◽

Seyedeh-Khadijeh Hashemi ◽

Manju Nidagodu Jayakumar ◽

Mitzi Nagarkatti ◽

Prakash Nagarkatti ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Mononuclear Cells ◽

Cultured Cells ◽

Inflammatory Responses ◽

Human Peripheral Blood ◽

Stimulation Index ◽

Tgf Beta ◽

Peripheral Blood Mononuclear

Regulatory T cells (Tregs) are key players in the regulation of inflammatory responses. In this study, two natural molecules, namely, sparteine sulfate (SS) and harpagoside (Harp), were investigated for their ability to induce Tregs in human peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from healthy volunteers and grown in the presence or absence of ConA, with TGF-beta, SS or Harp. Expression of the mRNA of FoxP3, TGF-beta, IL-10 and GAPDH was assessed via q-PCR. The expression of Treg markers including CD4, CD25, CD127 and FoxP3 was measured via flow cytometry. The secretion of IL-10 and TGF-beta by cultured cells was assessed by ELISA. Furthermore, the suppressive role of SS and Harp on PBMCs in vitro was tested via allogeneic mixed lymphocyte reaction (MLR). Data obtained show that both compounds increased the expression of FoxP3, TGF-beta and IL-10 mRNA in resting PBMCs but to a lesser extent in activated cells. Moreover, they significantly increased the percent of CD4+CD25+FoxP3+CD127− Tregs in activated and naïve PBMCs. Functionally, both compounds caused a significant reduction in the stimulation index in allogeneic MLR. Together, our data demonstrate for the first time that SS and Harp can induce human Tregs in vitro and therefore have great potential as anti-inflammatory agents.

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Suppression of NK Cell-Mediated Bone Marrow Cell Rejection by CD4+CD25+ Regulatory T Cells: Linkage of Adaptive to Innate Responses.

Blood ◽

10.1182/blood.v106.11.2195.2195 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2195-2195

Author(s):

William J. Murphy ◽

Isabel Bareo ◽

Alan M. Hanash ◽

Lisbeth A. Welniak ◽

Kai Sun ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Regulatory T Cells ◽

Cell Function ◽

Nk Cell ◽

Marrow Cell ◽

Poly I:C ◽

Hybrid Resistance

Abstract While a link between the innate to adaptive immune system has been established, studies demonstrating direct effects of T cells in regulating Natural Killer (NK) cell function have been lacking. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) have been shown to potently inhibit adaptive responses by T cells. We therefore investigated whether Tregs could affect NK cell function in vivo. Using a bone marrow transplantation (BMT) model of hybrid resistance, in which parental (H2d) marrow grafts are rejected by the NK cells of the F1 recipients (H2bxd), we demonstrate that the in vivo removal of host Tregs significantly enhances NK-cell mediated BM rejection. This heightened rejection was mediated by the specific NK cell Ly-49+ subset previously demonstrated to reject the BMC in this donor/host pairing. The depletion of Tregs could also further increase rejection already enhanced by treating recipients with the NK cell activator, poly I:C. Although splenic NK cell numbers were not significantly altered, increased splenic NK in vitro cytotoxic activity was observed from the recovered cells. The regulatory role of Tregs was confirmed in adoptive transfer studies in which transferred CD4+CD25+ Tregs resulted in abrogation of NK cell-mediated hybrid resistance. Thus, Tregs can potently inhibit NK cell function in vivo and their depletion may have therapeutic ramifications with NK cell function in BMT and cancer therapy.

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Leflunomide induces immunosuppression in collagen-induced arthritis rats by upregulating CD4+CD25+ regulatory T cells

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y09-094 ◽

2010 ◽

Vol 88 (1) ◽

pp. 45-53 ◽

Cited By ~ 11

Author(s):

Ting-Yu Wang ◽

Jun Li ◽

Chang-Yu Li ◽

Yong Jin ◽

Xiong-Wen Lü ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Regulatory T Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Con A ◽

Collagen Induced Arthritis ◽

Foxp3 Mrna ◽

Tgf Β1

This study was to investigate the effect of leflunomide on the immunosuppressive CD4+CD25+ regulatory T cells (CD4+CD25+ Tregs) in collagen-induced arthritis (CIA) rats. CIA was induced by collagen type II in Wistar rats. Immunofluorescence flow cytometry and RT-PCR were used to determine the proportion of CD4+CD25+ Tregs and the expression of Foxp3 mRNA, respectively. Proliferation of T lymphocytes was assayed with MTT reagent, and the level of transforming growth factor β1 (TGF-β1) in the supernatant of concanavalin A (Con A)-induced T lymphocytes was determined by ELISA kit. Our investigations demonstrated that inhibition of arthritis by leflunomide was related to changes in CD4+CD25+ Tregs. In addition, A771726, which is the active metabolite of leflunomide, promoted the differentiation of spleen lymphocytes into CD4+CD25+ Tregs, increased antiinflammatory cytokine TGF-β1 secretion, and adjusted the activity of Con A-induced lymphocytes in vitro.

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Effects of Portabella mushrooms on collagen-induced arthritis, inflammatory cytokines, and body composition in dilute brown non-agouti (DBA1) mice

Functional Foods in Health and Disease ◽

10.31989/ffhd.v1i9.123 ◽

2011 ◽

Vol 1 (9) ◽

pp. 279

Author(s):

Sandra Peterson ◽

Edralin A. Lucas ◽

Djibril Traore ◽

Lawrance Christopher ◽

Christine French ◽

...

Keyword(s):

Body Composition ◽

Mass Loss ◽

Inflammatory Cytokines ◽

Fat Mass ◽

Lean Mass ◽

Cell Function ◽

Bone Erosion ◽

Collagen Induced Arthritis ◽

Tnf Α

Background: Exotic mushrooms have long been used in Asia for treatment and/or prevention of chronic diseases due to their immunomodulatory properties. However, the health benefits of portabella mushrooms (PM) (brown Agaricus bisporous), on collagen-induced arthritis (CIA) and associated complications, (i.e. loss of lean mass, increased fat mass and inflammatory cytokines), have not been previously investigated.Methods: We investigated CIA pathogenesis, body composition and plasma levels of IL- 6, TNF-α and sICAM1 in DBA1 female mice fed either the AIN76 diet or the same diet fortified with 5% lyophilized PM (n=19-20/group). Ten mice/group were immunized with 100 µg bovine collagen type II on day 42 of the protocol, followed by 50 µg lipopolysaccharides on day 62, and euthanized on day 73-74. Cytokines were measured by ELISA.Results: Compared to baseline diet, PM had: no protective effect from CIA since all collagen-immunized mice developed severe edema, bone erosion, and mononuclear cell infiltration in paws. In mice with and those without CIA, feeding a PM-fortified diet resulted in higher percent of body fat than feeding the baseline diet (p<0.05). After CIA induction, PM provided the following beneficial effects: (a) a smaller reduction in lean mass and absolute thymus weight; (b) a higher fat mass loss; and (c) lower plasma TNF-α levels (p <0.05). PM-fortification did not alter plasma IL-6 and sICAM1 regardless of CIA status; but it increased in vitro IL-6 secretion by mitogen-treated spleen cells.Conclusion: Our data suggest that PM may reduce plasma TNF-α, attenuate lean mass loss and thymus atrophy associated with arthritis, and protect spleen cell function assessed by IL-6 secretion. However, PM-fortification did not attenuate overall CIA pathogenesis which may be due to lack of effect on plasma IL-6. Decreased TNF-α without alterations in IL-6 may reduce the risk of other conditions associated with chronic inflammation such as cardiovascular disease.Key words: portabella mushrooms, inflammatory cytokines, collagen-induced arthritis, body composition, TNF-α, IL-6, thymus, DBA1 mice.

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Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells

Leukemia ◽

10.1038/s41375-019-0625-3 ◽

2019 ◽

Vol 34 (3) ◽

pp. 895-908 ◽

Cited By ~ 2

Author(s):

Christin Riegel ◽

Tina J. Boeld ◽

Kristina Doser ◽

Elisabeth Huber ◽

Petra Hoffmann ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Therapeutic Potential ◽

Lymphoid Tissues ◽

Allogeneic Bone ◽

Efficient Treatment ◽

Target Organs ◽

Treg Population ◽

Life Threatening

Abstract Acute graft-versus-host disease (aGvHD) is a frequent complication after allogeneic bone marrow/stem cell transplantation (BMT/SCT) induced by co-transplanted alloreactive conventional donor T cells. We previously demonstrated that the adoptive transfer of donor CD4+CD25+Foxp3+ regulatory T cells (Treg) at the time of BMT prevents aGvHD in murine models. Yet, the therapeutic potential of donor Treg for the treatment of established aGvHD has not yet been studied in detail. We now used in vitro expanded phenotypically and functionally stable murine Treg to explore their therapeutic efficacy in haploidentical aGvHD models. Upon transfer donor Treg ameliorate clinical and histologic signs of aGvHD and significantly improve survival. They migrate to lymphoid as well as aGvHD target organs, predominantly the gastrointestinal tract, where they inhibit the proliferation of conventional T cells, reduce the influx of myeloid cells, and the accumulation of inflammatory cytokines. Successfully treated animals restore aGvHD-induced tissue damage in target organs and lymphoid tissues, thereby supporting lymphocyte reconstitution. The therapeutically applied Treg population survives long term without conversion into pathogenic effector T cells. These results demonstrate that donor Treg not only prevent aGvHD, but are also efficacious for the treatment of this life-threatening BMT complication.

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Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia

Journal of Experimental Medicine ◽

10.1084/jem.20050085 ◽

2005 ◽

Vol 201 (11) ◽

pp. 1793-1803 ◽

Cited By ~ 271

Author(s):

Claudia R. Ruprecht ◽

Marco Gattorno ◽

Francesca Ferlito ◽

Andrea Gregorio ◽

Alberto Martini ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Synovial Fluid ◽

Regulatory T Cells ◽

Cell Function ◽

Effector T Cells ◽

T Cell Proliferation ◽

Activated T Cells

A better understanding of the role of CD4+CD25+ regulatory T cells in disease pathogenesis should follow from the discovery of reliable markers capable of discriminating regulatory from activated T cells. We report that the CD4+CD25+ population in synovial fluid of juvenile idiopathic arthritis (JIA) patients comprises both regulatory and effector T cells that can be distinguished by expression of CD27. CD4+CD25+CD27+ cells expressed high amounts of FoxP3 (43% of them being FoxP3+), did not produce interleukin (IL)-2, interferon-γ, or tumor necrosis factor, and suppressed T cell proliferation in vitro, being, on a per cell basis, fourfold more potent than the corresponding peripheral blood population. In contrast, CD4+CD25+CD27− cells expressed low amounts of FoxP3, produced effector cytokines and did not suppress T cell proliferation. After in vitro activation and expansion, regulatory but not conventional T cells maintained high expression of CD27. IL-7 and IL-15 were found to be present in synovial fluid of JIA patients and, when added in vitro, abrogated the suppressive activity of regulatory T cells. Together, these results demonstrate that, when used in conjunction with CD25, CD27 is a useful marker to distinguish regulatory from effector T cells in inflamed tissues and suggest that at these sites IL-7 and IL-15 may interfere with regulatory T cell function.

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