TGF-β-Induced CD8+CD103+ Regulatory T Cells Show Potent Therapeutic Effect on Chronic Graft-versus-Host Disease Lupus by Suppressing B Cells

Lupus nephritis is one of most severe complications of systemic erythematosus lupus and current approaches are not curative for lupus nephritis. Although CD4+Foxp3+ regulatory T cells (Treg) are crucial for prevention of autoimmunity, the therapeutic effect of these cells on lupus nephritis is not satisfactory. We previously reported that CD8+CD103+ Treg induced ex vivo with TGF-β1 and IL-2 (CD8+CD103+ iTreg), regardless of Foxp3 expression, displayed potent immunosuppressive effect on Th cell response and had therapeutic effect on Th cell-mediated colitis. Here, we tested whether CD8+CD103+ iTreg can ameliorate lupus nephritis and determined potential molecular mechanisms. Adoptive transfer of CD8+CD103+ iTreg but not control cells to chronic graft-versus-host disease with a typical lupus syndrome showed decreased levels of autoantibodies and proteinuria, reduced renal pathological lesions, lowered renal deposition of IgG/C3, and improved survival. CD8+CD103+ iTreg cells suppressed not only T helper cells but also B cell responses directly that may involve in both TGF-β and IL-10 signals. Using RNA-seq, we demonstrated CD8+CD103+ iTreg have its own unique expression profiles of transcription factors. Thus, current study has identified and extended the target cells of CD8+CD103+ iTreg and provided a possible application of this new iTreg subset on lupus nephritis and other autoimmune diseases.

• Publication year

  2018

• Venue

  Frontiers in Immunology

• Publication date

  2018-01-30

• Fields of study

  Medicine

• Identifiers
  DOI 10.3389/fimmu.2018.00035PMID 29441062PMCID 5797539
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• TGF-β–Induced Regulatory T Cells Directly Suppress B Cell Responses through a Noncytotoxic Mechanism

  2016cited by this paper
• Systemic lupus erythematosus diagnosis and management

  2016cited by this paper
• Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial

  2016influential reference
• Interleukin 6 Accelerates Mortality by Promoting the Progression of the Systemic Lupus Erythematosus-Like Disease of BXSB.Yaa Mice

  2016cited by this paper
• Integrin αE(CD103) Is Involved in Regulatory T-Cell Function in Allergic Contact Hypersensitivity.

  2015cited by this paper
• Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

  2015cited by this paper
• CD8+CD122+ T-Cells: A Newly Emerging Regulator with Central Memory Cell Phenotypes

  2015cited by this paper
• TGF-β–Induced CD4+Foxp3+ T Cells Attenuate Acute Graft-versus-Host Disease by Suppressing Expansion and Killing of Effector CD8+ Cells

  2014cited by this paper
• Contributions of B cells to lupus pathogenesis.

  2014cited by this paper
• Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions

  2014cited by this paper
• Phenotypic and functional characteristic of a newly identified CD8+ Foxp3- CD103+ regulatory T cells.

  2014cited by this paper
• Differential role of all‐trans retinoic acid in promoting the development of CD4+ and CD8+ regulatory T cells

  2014cited by this paper
• Foxp3+ Treg cells in the inflamed CNS are insensitive to IL‐6‐driven IL‐17 production

  2012cited by this paper
• Polyclonal CD4+Foxp3+ Treg cells induce TGFβ-dependent tolerogenic dendritic cells that suppress the murine lupus-like syndrome.

  2012cited by this paper
• Antigen-specific transforming growth factor β-induced Treg cells, but not natural Treg cells, ameliorate autoimmune arthritis in mice by shifting the Th17/Treg cell balance from Th17 predominance to Treg cell predominance.

  2012cited by this paper
• Induced Foxp3(+) regulatory T cells: a potential new weapon to treat autoimmune and inflammatory diseases?

  2012cited by this paper
• Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells

  2012cited by this paper
• A Regulatory Role for IL-10 Receptor Signaling in Development and B Cell Help of T Follicular Helper Cells in Mice

  2012influential reference
• B Cells in Autoimmune Diseases

  2012cited by this paper
• Lupus nephritis: current update

  2011cited by this paper
• Cutting Edge: All-Trans Retinoic Acid Sustains the Stability and Function of Natural Regulatory T Cells in an Inflammatory Milieu

  2010cited by this paper
• Rituximab, B-lymphocyte depletion, and preservation of beta-cell function.

  2009cited by this paper
• Cutting Edge: Regulatory T Cells Directly Suppress B Cells in Systemic Lupus Erythematosus1

  2009influential reference
• Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo

  2009cited by this paper
• CD8(+)CD103(+) regulatory T cells in spontaneous tolerance of liver allografts.

  2009cited by this paper
• New approaches of B-cell-directed therapy: beyond rituximab

  2008cited by this paper
• Regulatory T cells and immune tolerance.

  2008cited by this paper
• Cutting Edge: Foxp3+CD4+CD25+ Regulatory T Cells Induced by IL-2 and TGF-β Are Resistant to Th17 Conversion by IL-61

  2008cited by this paper
• Th3 Cells in Peripheral Tolerance. II. TGF-β-Transgenic Th3 Cells Rescue IL-2-Deficient Mice from Autoimmunity1

  2007cited by this paper
• Cutting Edge: Regulatory T Cells Induce CD4+CD25−Foxp3− T Cells or Are Self-Induced to Become Th17 Cells in the Absence of Exogenous TGF-β

  2007cited by this paper
• IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells1

  2007cited by this paper
• Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression

  2007cited by this paper
• Th3 Cells in Peripheral Tolerance. I. Induction of Foxp3-Positive Regulatory T Cells by Th3 Cells Derived from TGF-β T Cell-Transgenic Mice1

  2007cited by this paper
• Epigenetic Control of the foxp3 Locus in Regulatory T Cells

  2007cited by this paper
• Orphanet Journal of Rare Diseases BioMed Central Review

  2006cited by this paper
• TGF-β Requires CTLA-4 Early after T Cell Activation to Induce FoxP3 and Generate Adaptive CD4+CD25+ Regulatory Cells1

  2006cited by this paper
• Suppression of Disease in New Zealand Black/New Zealand White Lupus-Prone Mice by Adoptive Transfer of Ex Vivo Expanded Regulatory T Cells1

  2006cited by this paper
• CD8+ T regulatory cells use a novel genetic program that includes CD103 to suppress Th1 immunity in eye-derived tolerance.

  2006cited by this paper
• Comment on “CD226 Is Specifically Expressed on the Surface of Th1 Cells and Regulates Their Expansion and Effector Functions”

  2006cited by this paper
• Activated CD4+CD25+ T cells selectively kill B lymphocytes.

  2006influential reference
• CD103 Is a Marker for Alloantigen-Induced Regulatory CD8+ T Cells

  2006cited by this paper
• RANK and RANKL expression as markers of dendritic cell-T cell interactions in paired samples of rheumatoid synovium and lymph nodes.

  2005cited by this paper
• Cutting Edge: Direct Suppression of B Cells by CD4+CD25+ Regulatory T Cells1

  2005cited by this paper
• CD4+ and CD8+ Regulatory T Cells Generated Ex Vivo with IL-2 and TGF-β Suppress a Stimulatory Graft-versus-Host Disease with a Lupus-Like Syndrome1

  2004cited by this paper
• Regulation of CD103 Expression by CD8+ T Cells Responding to Renal Allografts 1

  2004cited by this paper
• Natural and Induced CD4+CD25+ Cells Educate CD4+CD25− Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-101

  2004cited by this paper
• Cutting Edge: Cure of Colitis by CD4+CD25+ Regulatory T Cells1

  2003cited by this paper
• Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells

  2003cited by this paper
• Regulation of Mucosal Dendritic Cell Function by Receptor Activator of NF-κB (RANK)/RANK Ligand Interactions: Impact on Tolerance Induction

  2002cited by this paper
• Generation Ex Vivo of TGF-β-Producing Regulatory T Cells from CD4+CD25− Precursors1

  2002cited by this paper
• Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity

  2001cited by this paper
• Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages.

  2001cited by this paper
• TGF-β Receptor Controls B Cell Responsiveness and Induction of IgA In Vivo

  2000cited by this paper
• TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo.

  2000influential reference
• Regulation of the epithelial cell-specific integrin, CD103, by human CD8+ cytolytic T lymphocytes.

  1999cited by this paper
• A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis

  1997cited by this paper
• Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

  1995cited by this paper
• Polyclonal B cell activation arises from different mechanisms in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice.

  1993cited by this paper
• A molecular biologic study of extracellular matrix components during the development of glomerulosclerosis in murine chronic graft-versus-host disease.

  1992cited by this paper
• Lupus nephritis. Part I. Histopathological classification, activity and chronicity scores.

  1991cited by this paper
• Murine chronic graft-versus-host disease as a model for lupus nephritis.

  1988cited by this paper
• Increased spontaneous activity of antibody-forming cells in the peripheral blood of patients with active SLE.

  1977cited by this paper

• TGF-β signaling mediates crosstalk between CD8+ T cells and CD39+ induced Treg cells in autoimmune inflammation

  2026cites this paper
• The role of CD36 in immune function: bridging innate and adaptive responses

  2026cites this paper
• Cytotoxic T Cells: Kill, Memorize, and Mask to Maintain Immune Homeostasis

  2025cites this paper
• The role of B cells in Sjögren's syndrome and their impact on the nervous system.

  2025cites this paper
• Revolutionizing Autoimmune Kidney Disease Treatment with Chimeric Antigen Receptor-T Cell Therapy

  2025cites this paper
• A donor PD-1+CD8+ TSCM-like regulatory subset mobilized by G-CSF alleviates recipient acute graft-versus-host-disease

  2025cites this paper
• Foxp3+CD8+ regulatory T cells: bona fide Tregs with cytotoxic function.

  2025cites this paper
• Role of regulatory T cells in inflammatory liver diseases.

  2025cites this paper
• Single mutation tunes IRF4 function and mediates B cell character to ameliorate murine lupus

  2025cites this paper
• CD8 + CD103 + iTregs protect against ischemia-reperfusion-induced acute kidney Injury by inhibiting pyroptosis

  2024cites this paper
• An angel or a devil? Current view on the role of CD8+ T cells in the pathogenesis of myasthenia gravis

  2024cites this paper
• Immunological characteristics of CD103+CD8+ Tc cells in the liver of C57BL/6 mouse infected with plasmodium NSM

  2023cites this paper
• Th1-related transcription factors and cytokines in systemic lupus erythematosus

  2023cites this paper
• Teriflunomide induces Foxp3 expression in murine CD8 + T cells while IL-27 and retinoic acid exert a synergistic effect on the induction of CD39 expression on these cells.

  2023cites this paper
• CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential

  2023cites this paper
• Research progress on CD8 + T cell immune regulation in allogenic transplantation.

  2023cites this paper
• Pathogenic cellular and molecular mediators in lupus nephritis

  2023cites this paper
• BET-bromodomain and EZH2 inhibitor treated chronic GVHD mice have blunted germinal centers with distinct transcriptomes.

  2022cites this paper
• Research advances on targeted-Treg therapies on immune-mediated kidney diseases.

  2022cites this paper
• SB431542 alleviates lupus nephritis by regulating B cells and inhibiting the TLR9/TGFβ1/PDGFB signaling.

  2022cites this paper
• Cytolytic CD4+ and CD8+ Regulatory T-Cells and Implications for Developing Immunotherapies to Combat Graft-Versus-Host Disease

  2022influential citation
• Systemic lupus erythematosus patients contain B‐cell receptor repertoires sensitive to immunosuppressive drugs

  2022cites this paper
• Newly Found Peacekeeper: Potential of CD8+ Tregs for Graft-Versus-Host Disease

  2021influential citation
• Regulatory T Cells: Concept, Classification, Phenotype, and Biological Characteristics.

  2021cites this paper
• Tregs in Autoimmune Uveitis.

  2021cites this paper
• Harnessing Tolerogenic Histone Peptide Epitopes From Nucleosomes for Selective Down-Regulation of Pathogenic Autoimmune Response in Lupus (Past, Present, and Future)

  2021cites this paper
• Therapeutic Effect of Mesenchymal Stem Cells on Sjögren's Syndrome: Systematic Review and a Preclinical Meta-Analysis

  2021cites this paper
• Intestinal cDC1 drive cross-tolerance to epithelial-derived antigen via induction of FoxP3+CD8+ Tregs

  2021influential citation
• Role of tissue-resident memory T cells in the pathophysiology of allergic contact dermatitis

  2021cites this paper
• A narrative review of PD-1 and autoimmune diseases

  2021cites this paper
• CD8+ Regulatory T Cell – A Mystery to Be Revealed

  2021cites this paper
• Nuclear Factor κB (NF-κB)–Mediated Inflammation in Multiple Sclerosis

  2020cites this paper
• Rôle des lymphocytes T résidents mémoires dans la physiopathologie des eczémas allergiques de contact

  2020cites this paper
• An updated advance of autoantibodies in autoimmune diseases.

  2020cites this paper
• Endothelial dysfunction and cardiovascular risk in lupus nephritis: New roles for old players?

  2020cites this paper
• Nucleic Acid-Based Approaches for Tumor Therapy

  2020cites this paper
• CD103 Promotes the Pro-inflammatory Response of Gastric Resident CD4+ T Cell in Helicobacter pylori-Positive Gastritis

  2020cites this paper
• The possible linkage of granzyme B-producing skin T cells with the disease prognosis of alopecia areata.

  2020cites this paper
• Human gingiva-derived mesenchymal stem cells are therapeutic in lupus nephritis through targeting of CD39-CD73 signaling pathway.

  2020cites this paper
• Update on T cells in the virally infected brain: friends and foes

  2020cites this paper
• CD19+CD24hiCD38hi regulatory B cells: a potential immune predictive marker of severity and therapeutic responsiveness of hepatitis C.

  2020cites this paper
• High salt diet accelerates the progression of murine lupus through dendritic cells via the p38 MAPK and STAT1 signaling pathways

  2020cites this paper
• Differential roles of TNFα-TNFR1 and TNFα-TNFR2 in the differentiation and function of CD4+Foxp3+ induced Treg cells in vitro and in vivo periphery in autoimmune diseases

  2019cites this paper
• CD8+CD103+ iTregs Inhibit Chronic Graft-versus-Host Disease with Lupus Nephritis by the Increased Expression of CD39

  2019cites this paper
• Cell Therapy in Solid Organ Transplantation.

  2019cites this paper
• CD8+CD103+ iTregs inhibit the progression of lupus nephritis by attenuating glomerular endothelial cell injury.

  2019cites this paper
• FKN Facilitates HK-2 Cell EMT and Tubulointerstitial Lesions via the Wnt/β-Catenin Pathway in a Murine Model of Lupus Nephritis

  2019cites this paper
• Blockade of miR-142-3p promotes anti-apoptotic and suppressive function by inducing KDM6A-mediated H3K27me3 demethylation in induced regulatory T cells

  2019cites this paper
• The expanding family of noncanonical regulatory cell subsets

  2019cites this paper
• The essential role of costimulatory molecules in systemic lupus erythematosus

  2019cites this paper
• Parasitic Worms for the Treatment of Neurodegeneration

  2019cites this paper
• Advances in the clinical and mechanism research of pollen induced seasonal allergic asthma.

  2019cites this paper
• Graft-Versus-Host Disease

  2019cites this paper
• Tc17/IL-17A Up-Regulated the Expression of MMP-9 via NF-κB Pathway in Nasal Epithelial Cells of Patients With Chronic Rhinosinusitis

  2018cites this paper
• Stabilization of Foxp3 by Targeting JAK2 Enhances Efficacy of CD8 Induced Regulatory T Cells in the Prevention of Graft-versus-Host Disease

  2018cites this paper
• CD8+iTregs attenuate glomerular endothelial cell injury in lupus‐prone mice through blocking the activation of p38 MAPK and NF‐&kgr;B

  2018cites this paper
• Alkannin protects human renal proximal tubular epithelial cells from LPS-induced inflammatory injury by regulation of microRNA-210.

  2018cites this paper
• The Emerging Role of CD8+ Tissue Resident Memory T (TRM) Cells in Antitumor Immunity: A Unique Functional Contribution of the CD103 Integrin

  2018cites this paper
• Update of humanized animal disease models in studying Graft-versus-host disease

  2018cites this paper