Differential effects of rapamycin and retinoic acid on expansion, stability and suppressive qualities of human CD4+CD25+FOXP3+ T regulatory cell subpopulations

Scottà, Cristiano; Esposito, Marianna; Fazekasova, Henrieta; Fanelli, Giorgia; Edozie, Francis C.; Ali, Nasreen; Xiao, Fang; Peakman, Mark; Afzali, Behdad; Sagoo, Pervinder; Lechler, Robert I.; Lombardi, Giovanna

doi:10.3324/haematol.2012.074088

Cited by 129 publications

(161 citation statements)

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“…Although it has been demonstrated that RA contributes to the expansion and generation of Tregs [43][44][45][46], RA has also been shown to be responsible for the induction of the gut-homing receptors α4β7 and CCR9 on T cells [34,35]. In our study, we observed that physiological concentrations of RA and IL-2 did induce the expression of gut-homing receptors.…”

Section: Discussionsupporting

confidence: 59%

“…Notably, in these in vivo experiments, RA-iTreg cells were not separated from the small population of activated effector T cells present in the cultures during their generation. These results further support the hypothesis that RA-iTreg cells hold potent suppressive capacity in vivo.The future translation of our protocol using TGF-β, IL-2, and RA for use in cellular therapy approaches is supported by the observations that RA is able to expand/generate human Foxp3 + Treg cells with potent suppressive ability from Treg cells [43,44] and naïve T cells [44][45][46]. Moreover, the generation of alloreactive Treg cells from non-Treg precursors by stimulation with alloantigens may offer immunological advantages over polyclonal expansion of naturally occurring Treg cells, as indicated by other authors [67,68].…”

mentioning

confidence: 89%

“…For instance, it has been demonstrated that RA contributes to the expansion of Foxp3 + Treg cells [43,44] and enhances Treg-cell differentiation from naïve T cells [44][45][46]. However, the role of RA in inducing allogeneic Treg cells with potent suppressive capacity and presenting an unbiased homing potential has not been studied in detail.…”

Section: Introductionmentioning

confidence: 99%

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Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

et al. 2014

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CD4 + CD25 + Foxp3 + regulatory T (Treg) cells mediate immunological self-tolerance and suppress immune responses. Retinoic acid (RA), a natural metabolite of vitamin A, has been reported to enhance the differentiation of Treg cells in the presence of TGF-β. In this study, we show that the co-culture of naive T cells from C57BL/6 mice with allogeneic antigen-presenting cells (APCs) from BALB/c mice in the presence of TGF-β, RA, and IL-2 resulted in a striking enrichment of Foxp3 + T cells. These RA in vitro-induced regulatory T (RA-iTreg) cells did not secrete Th1-, Th2-, or Th17-related cytokines, showed a nonbiased homing potential, and expressed several cell surface molecules related to Treg-cell suppressive potential. Accordingly, these RA-iTreg cells suppressed T-cell proliferation and inhibited cytokine production by T cells in in vitro assays. Moreover, following adoptive transfer, RA-iTreg cells maintained Foxp3 expression and their suppressive capacity. Finally, RA-iTreg cells showed alloantigen-specific immunosuppressive capacity in a skin allograft model in immunodeficient mice. Altogether, these data indicate that functional and stable allogeneic-specific Treg cells may be generated using TGF-β, RA, and IL-2. Thus, RA-iTreg cells may have a potential use in the development of more effective cellular therapies in clinical transplantation. Keywords: Allogeneic regulatory T cells r Homing r Retinoic acid r Tolerance r TransplantationAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionRegulatory T (Treg) cells are responsible for inducing and maintaining peripheral tolerance [1]. Treg cells are classified into two Correspondence: Dr. Daniela Sauma e-mail: dsauma@u.uchile.cl major subpopulations: thymus-derived Treg cells, which are generated in the thymus and circulate in the periphery as functional mature Treg cells [2][3][4], and peripherally derived Treg cells, which are generated in the periphery from CD4 + CD25 − naive * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 452-463 Immunomodulation 453T cells [5][6][7]. Treg cells target effector T cells and dendritic cells (DCs) by modulating their maturation and function through several mechanisms that suppress immune responses [8][9][10]; these include secretion of inhibitory cytokines (IL-10, IL-35, and TGF-β), granzyme/perforin-dependent mediated cytolysis, metabolic disruption [11][12][13][14][15], and the expression of LAG3 and CTLA4, which alter DC function [16,17]. In addition to the aforementioned mechanisms, Treg-cell suppressive capacity is dependent on Treg-cell migration and retention in the microenvironment where regulation is required. Differential expression patterns of chemokine receptors (such as CCR4, CCR5, and CCR9), integrins (α4β7), and selectins (CD62L) contribute to selective retention and trafficking of Treg cells and allow their appropriate localization during ...

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Section: Discussionsupporting

confidence: 59%

mentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

et al. 2014

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“…Nevertheless, this finding is the clearest indication yet that Treg-based cell therapy for renal allograft transplantation should use a Rapamycin-based protocol. Rapamycin is an ideal choice for Treg-based therapy in solid organ transplantation, because it preferentially expands the most stable Treg subpopulation (population I) and inhibits IL-17 production from other subpopulations (32,44). Rapamycin interferes with early T cell signaling events (Akt/mammalian target of rapamycin), which are critical in T cell fate decisions (45).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Regulatory T Cells in Hemodialysis Patients and Healthy Controls

Afzali

Edozie

Fazekasova

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Cell-based therapy with natural (CD4 + CD25 hi CD127 lo ) regulatory T cells to induce transplant tolerance is now technically feasible. However, regulatory T cells from hemodialysis patients awaiting transplantation may be functionally/numerically defective. Human regulatory T cells are also heterogeneous, and some are able to convert to proinflammatory Th17 cells. This study addresses the suitability of regulatory T cells from hemodialysis patients for cell-based therapy in preparation for the first clinical trials in renal transplant recipients (the ONE Study).Design, setting, participants, & measurements Healthy controls and age-and sex-matched hemodialysis patients without recent illness/autoimmune disease on established, complication-free hemodialysis for a minimum of 6 months were recruited. Circulating regulatory T cells were studied by flow cytometry to compare the regulatory T cell subpopulations. Regulatory T cells from members of each group were compared for suppressive function and plasticity (IL-17-producing capacity) before and after in vitro expansion with and without Rapamycin, using standard assays.Results Both groups had similar total regulatory T cells and subpopulations I and III. In each subpopulation, regulatory T cells expressed similar levels of the function-associated markers CD27, CD39, HLA-DR, and FOXP3. Hemodialysis regulatory T cells were less suppressive, expanded poorly compared with healthy control regulatory T cells, and produced IL-17 in the absence of Rapamycin. However, Rapamycin efficiently expanded hemodialysis regulatory T cells to a functional and stable cell product.Conclusions Rapamycin-based expansion protocols should enable clinical trials of cell-based immunotherapy for the induction of tolerance to renal allografts using hemodialysis regulatory T cells.

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“…40,41 It remains unclear whether RAPA selectively suppresses the expansion of non-Treg cells, thereby indirectly promoting the expansion of Foxp3 1 Treg cells. 16 Although a comparison study has shown that both RAPA and atRA had similar effects on promoting and stabilizing Treg cells during their expansion, 42 a more recent study demonstrated that atRA exhibits superior efficacy relative to RAPA for stabilizing nTreg cells under inflammatory conditions. 23 The mechanism by which atRA stabilizes nTreg cells is discussed below.…”

Section: Foxp3 and Treg Cell Subsetsmentioning

confidence: 99%

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

Liu

Wang

et al. 2015

Cell Mol Immunol

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Regulatory T (Treg) cells are necessary for immune system homeostasis and the prevention of autoimmune diseases. Foxp3 is specifically expressed in Treg cells and plays a key role in their differentiation and function. Foxp3 1 Treg cells are consisted of naturally occurring, thymus-derived Treg (nTreg) and peripheral-induced Treg (iTreg) cells that may have different functional characteristics or synergistic roles. All-trans retinoic acid (atRA), a vitamin A metabolite, regulates a wide range of biological processes, including cell differentiation and proliferation. Recent studies demonstrated that atRA also regulates the differentiation of T helper (Th) cells and Treg cells. Moreover, atRA also sustains nTreg stability under inflammatory conditions. In this review, we summarize the significant progress of our understanding of the role(s) and mechanisms of atRA in Treg biology.

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Differential effects of rapamycin and retinoic acid on expansion, stability and suppressive qualities of human CD4+CD25+FOXP3+ T regulatory cell subpopulations

Cited by 129 publications

References 46 publications

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

Comparison of Regulatory T Cells in Hemodialysis Patients and Healthy Controls

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

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