Rapamycin and abundant TCR stimulation are required for the generation of stable human induced regulatory T cells

Regulatory T cells (Tregs) are a vital sub‐population of CD4+ T cells with major roles in immune tolerance and homeostasis. Given such properties, the use of regulatory T cells for immunotherapies has been extensively investigated, with a focus on adoptive transfer of ex vivo expanded natural Tregs (nTregs). For immunotherapies, induced Tregs (iTregs), generated in vitro from naïve CD4+ T cells, provide an attractive alternative, given the ease of generating cell numbers required for clinical dosage. While the combination of TGF‐β, ATRA and rapamycin has been shown to generate highly suppressive iTregs, the challenge for therapeutic iTreg generation has been their instability. Here, we investigate the impact of rapamycin concentrations and α‐CD3/CD28 bead ratios on human iTreg stability.

• Publication year

  2020

• Venue

  Clinical & Translational Immunology

• Publication date

  2020-12-14

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1002/cti2.1223PMID 33425354PMCID 7780108
• 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.

• Epigenetic conversion of conventional T cells into regulatory T cells by CD28 signal deprivation

  2020cited by this paper
• Past, Present, and Future of Regulatory T Cell Therapy in Transplantation and Autoimmunity

  2019cited by this paper
• Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg‐mediated suppression of cytokine expression

  2019cited by this paper
• Antigen-Specificity in the Thymic Development and Peripheral Activity of CD4+FOXP3+ T Regulatory Cells

  2018cited by this paper
• Time-resolved transcriptome and proteome landscape of human regulatory T cell (Treg) differentiation reveals novel regulators of FOXP3

  2018cited by this paper
• STAT5 and TET2 Cooperate to Regulate FOXP3-TSDR Demethylation in CD4+ T Cells of Patients with Colorectal Cancer

  2018cited by this paper
• TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity

  2018cited by this paper
• Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization

  2018cited by this paper
• Molecular Markers Distinguishing T Cell Subtypes With TSDR Strand-Bias Methylation

  2018cited by this paper
• Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity

  2017cited by this paper
• Architectural and functional alterations of the small intestinal mucosa in classical Whipple’s disease

  2017cited by this paper
• Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation

  2017cited by this paper
• Induced regulatory T cells are phenotypically unstable and do not protect mice from rapidly progressive glomerulonephritis

  2017cited by this paper
• IL-17A-Producing Foxp3+ Regulatory T Cells and Human Diseases

  2017cited by this paper
• Generation of RORγt+ Antigen-Specific T Regulatory 17 Cells from Foxp3+ Precursors in Autoimmunity.

  2017cited by this paper
• RORγt and RORα signature genes in human Th17 cells

  2017cited by this paper
• CCR8+FOXp3+ Treg cells as master drivers of immune regulation

  2017cited by this paper
• Pillars Article: Control of Regulatory T Cell Development by the Transcription Factor Foxp3. Science 2003. 299: 1057-1061.

  2017cited by this paper
• Functional heterogeneity of gut-resident regulatory T cells

  2017cited by this paper
• Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

  2017cited by this paper
• Comparative Analysis of Protocols to Induce Human CD4+Foxp3+ Regulatory T Cells by Combinations of IL-2, TGF-beta, Retinoic Acid, Rapamycin and Butyrate

  2016influential reference
• An essential role for IL-2 receptor in regulatory T cell function

  2016cited by this paper
• Induced Regulatory T Cells: Their Development, Stability, and Applications.

  2016influential reference
• T cell receptor signalling in the control of regulatory T cell differentiation and function

  2016cited by this paper
• Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

  2016cited by this paper
• Control of Foxp3 stability through modulation of TET activity

  2016cited by this paper
• Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family.

  2016cited by this paper
• Regulatory T Cells: Serious Contenders in the Promise for Immunological Tolerance in Transplantation

  2015cited by this paper
• Epigenetic analysis of regulatory T cells using multiplex bisulfite sequencing

  2015cited by this paper
• Molecular and cellular insights into T cell exhaustion

  2015cited by this paper
• Ex Vivo–Expanded but Not In Vitro–Induced Human Regulatory T Cells Are Candidates for Cell Therapy in Autoimmune Diseases Thanks to Stable Demethylation of the FOXP3 Regulatory T Cell–Specific Demethylated Region

  2015cited by this paper
• T cell subsets and their signature cytokines in autoimmune and inflammatory diseases.

  2015cited by this paper
• Reestablishment of Active Immunity against HBV Graft Reinfection after Liver Transplantation for HBV-Related End Stage Liver Disease

  2014cited by this paper
• The Treg-Specific Demethylated Region Stabilizes Foxp3 Expression Independently of NF-κB Signaling

  2014cited by this paper
• Rapamycin Regulates iTreg Function through CD39 and Runx1 Pathways

  2014cited by this paper
• Effect of Proinflammatory Cytokines (IL-6, TNF-α, and IL-1β) on Clinical Manifestations in Indian SLE Patients

  2014cited by this paper
• Regulatory T Cells as Immunotherapy

  2014cited by this paper
• mTOR signaling, Tregs and immune modulation.

  2014cited by this paper
• The effects of rapamycin on regulatory T cells: its potential time-dependent role in inducing transplant tolerance.

  2014cited by this paper
• Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

  2013cited by this paper
• Ex Vivo Expanded Human Regulatory T Cells Can Prolong Survival of a Human Islet Allograft in a Humanized Mouse Model

  2013influential reference
• Induced Regulatory T Cells Promote Tolerance When Stabilized by Rapamycin and IL-2 In Vivo

  2013cited by this paper
• Essentials of Th17 cell commitment and plasticity.

  2013cited by this paper
• Generation and Function of Induced Regulatory T Cells

  2013influential reference
• Peripherally Induced Tregs – Role in Immune Homeostasis and Autoimmunity

  2013cited by this paper
• TGF-β: Guardian of T Cell Function

  2013cited by this paper
• Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells.

  2012cited by this paper
• Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells.

  2012cited by this paper
• T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development.

  2012cited by this paper
• Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict.

  2012cited by this paper
• Nature and nurture in Foxp3(+) regulatory T cell development, stability, and function.

  2012cited by this paper
• Induced regulatory T cells: mechanisms of conversion and suppressive potential.

  2012cited by this paper
• The TCR Repertoires of Regulatory and Conventional T Cells Specific for the Same Foreign Antigen Are Distinct

  2012cited by this paper
• Molecular Mechanisms of Treg-Mediated T Cell Suppression

  2012cited by this paper
• Instability of Foxp3 Expression Limits the Ability of Induced Regulatory T Cells to Mitigate Graft versus Host Disease

  2011cited by this paper
• Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

  2011cited by this paper
• Expansion of CD4+CD25+ regulatory T cells from cord blood CD4+ cells using the common γ-chain cytokines (IL-2 and IL-15) and rapamycin

  2011cited by this paper
• Generation and Large‐Scale Expansion of Human Inducible Regulatory T Cells That Suppress Graft‐Versus‐Host Disease

  2011influential reference
• Regulatory T Cells

  2011cited by this paper
• Sub‐optimal CD4+ T‐cell activation triggers autonomous TGF‐β‐dependent conversion to Foxp3+ regulatory T cells

  2011cited by this paper
• Generation of human regulatory T cells de novo with suppressive function prevent xenogeneic graft versus host disease.

  2011influential reference
• Characterization of Protective Human CD4+CD25+ FOXP3+ Regulatory T Cells Generated with IL-2, TGF-β and Retinoic Acid

  2010influential reference
• Ex Vivo–Expanded Human Regulatory T Cells Prevent the Rejection of Skin Allografts in a Humanized Mouse Model

  2010cited by this paper
• Development of thymically derived natural regulatory T cells

  2010cited by this paper
• Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling.

  2010cited by this paper
• TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo

  2010cited by this paper
• Levels of Foxp3 in Regulatory T Cells Reflect Their Functional Status in Transplantation1

  2009cited by this paper
• The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment.

  2009cited by this paper
• De Novo Generation and Enhanced Suppression of Human CD4+CD25+ Regulatory T Cells by Retinoic Acid1

  2009cited by this paper
• DNA methylation controls Foxp3 gene expression

  2008cited by this paper
• The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells

  2008cited by this paper
• How regulatory T cells work

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

  2008cited by this paper
• Combination of rapamycin and IL-2 increases de novo induction of human CD4(+)CD25(+)FOXP3(+) T cells.

  2008cited by this paper
• CTLA-4 trafficking and surface expression.

  2008cited by this paper
• Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway.

  2008cited by this paper
• Regulation and Function of Proinflammatory TH17 Cells

  2008cited by this paper
• A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism

  2007cited by this paper
• Cutting Edge: Opposite Effects of IL-1 and IL-2 on the Regulation of IL-17+ T Cell Pool IL-1 Subverts IL-2-Mediated Suppression1

  2007cited by this paper
• Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation.

  2007cited by this paper
• DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells

  2007influential reference
• IL-2 Receptor β-Dependent STAT5 Activation Is Required for the Development of Foxp3+ Regulatory T Cells1

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

  2007cited by this paper
• Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production.

  2007cited by this paper
• Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

  2006cited by this paper
• CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells

  2006cited by this paper
• Inducing and expanding regulatory T cell populations by foreign antigen

  2005cited by this paper
• Supporting Online Material

  2003cited by this paper
• Foxp3 programs the development and function of CD4+CD25+ regulatory T cells

  2003cited by this paper
• CD4+CD25high Regulatory Cells in Human Peripheral Blood1

  2001cited by this paper
• CD4CD25 Regulatory Cells in Human Peripheral Blood

  2001cited by this paper
• Homeostasis of naive and memory T cell subpopulations in peripheral blood and lymphoid tissues in the context of human immunodeficiency virus infection.

  2001cited by this paper
• The Goldilocks conditions applied to T cell development

  2001cited 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
• Developmental and maturational changes in human blood lymphocyte subpopulations.

  1992cited by this paper
• Regulation of interleukin 6 production in T helper cells.

  1990cited by this paper

• Alternate splicing converts human CD137 from costimulatory to immunosuppressive function.

  2025cites this paper
• Immunomodulatory Role and Therapeutic Potential of HLA-DR+ Regulatory T Cells in Systemic Lupus Erythematosus

  2025cites this paper
• Regulatory T cells engineered with polyphenol-functionalized immunosuppressant nanocomplexes for rebuilding periodontal hard tissue under inflammation-challenged microenvironment.

  2024cites this paper
• Eras of designer Tregs: Harnessing synthetic biology for immune suppression

  2023cites this paper
• Molecular and therapeutic insights of rapamycin: a multi-faceted drug from Streptomyces hygroscopicus

  2023cites this paper
• Targeting FOXP3 Tumor-Intrinsic Effects Using Adenoviral Vectors in Experimental Breast Cancer

  2023cites this paper
• Transforming growth factor–β1 in regulatory T cell biology

  2022cites this paper
• Induction of stable human FOXP3+ Tregs by a parasite‐derived TGF‐β mimic

  2021cites this paper
• Nanoparticles Engineered as Artificial Antigen-Presenting Cells Induce Human CD4+ and CD8+ Tregs That Are Functional in Humanized Mice

  2021cites this paper