CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells

Cederbom, Lukas; Hall, Håkan; Ivars, Fredrik

doi:10.1002/1521-4141(200006)30:6<1538::aid-immu1538>3.0.co;2-x

Cited by 505 publications

(291 citation statements)

References 9 publications

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“…This idea is reinforced by the observation that in vitro suppression was abrogated in the presence of APCP, a CD73-specific inhibitor (data not shown). Another well-known suppressive function of Treg cells includes the control of DC maturation and activation by CTLA-4 and LAG-3 expression [62][63][64][65][66]. The high expression of these molecules by RA-iTreg cells supports the notion that these cells may regulate the immune response by also suppressing DC function.…”

Section: Discussionmentioning

confidence: 81%

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: Discussionmentioning

confidence: 81%

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

et al. 2014

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“…The Tol-DC subset possesses low levels of MHC class II, CD80/86, and IL-12, while secreting high levels of 20). In contrast, T cells that secrete TGF-␤ and IL-10 also can promote the generation of Tol-DC with immature phenotype (21,22). However, these studies are in vitro, and demonstrate a oneway regulation of Treg on Tol-DC and Tol-DC on Treg, respectively.…”

Section: Inhibitory Feedback Loop Between Tolerogenic Dendritic Cellsmentioning

confidence: 92%

“…It has been reported that CD4 ϩ CD25 ϩ cells can be generated in vitro by activation of naive T cells in the presence of immature DC that possess low levels of MHC class II, CD80/86, and IL-12, but secrete high levels of IL-10 (10, 20). In contrast, anergized T cells secreting TGF-␤ and IL-10 also can promote the generation of Tol-DC with immature phenotype (21,22). However, the mutual relationship between Tol-DC and Treg has never been investigated in transplant tolerance.…”

Section: Inhibitory Feedback Loop Between Tol-dc and Treg In Transplamentioning

confidence: 99%

Inhibitory Feedback Loop Between Tolerogenic Dendritic Cells and Regulatory T Cells in Transplant Tolerance

Min

Zhou

Ichim

et al. 2003

The Journal of Immunology

228

163

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An active role of T regulatory cells (Treg) and tolerogenic dendritic cells (Tol-DC) is believed important for the induction and maintenance of transplantation tolerance. However, interactions between these cells remain unclear. We induced donor-specific tolerance in a fully MHC-mismatched murine model of cardiac transplantation by simultaneously targeting T cell and DC function using anti-CD45RB mAb and LF 15-0195, a novel analog of the antirejection drug 15-deoxyspergualin, respectively. Increases in splenic Treg and Tol-DC were observed in tolerant recipients as assessed by an increase in CD4+CD25+ T cells and DC with immature phenotype. Both these cell types exerted suppressive effects in MLR. Tol-DC purified from tolerant recipients incubated with naive T cells induced the generation/expansion of CD4+CD25+ Treg. Furthermore, incubation of Treg isolated from tolerant recipients with DC progenitors resulted in the generation of DC with Tol-DC phenotype. Treg and Tol-DC generated in vitro were functional based on their suppressive activity in vitro. These results are consistent with the notion that tolerance induction is associated with a self-maintaining regulatory loop in which Tol-DC induce the generation of Treg from naive T cells and Treg programs the generation of Tol-DC from DC progenitors.

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“…In this context, it was demonstrated that DC cultured in the presence of IL-10 suppress the response of Ag-specific naive or activated CD4 + T cells and promote the generation of T regulatory cells [41,42]. CD4 + CD25 + regulatory T cells down-regulate costimulatory molecules on APC even in the presence of stimuli that would normally increase their expression [43]. Helminthinduced T regulatory cells play also an important role in the general state of immunosuppression observed in some infections [8][9][10].…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive components of Ascaris suum down‐regulate expression of costimulatory molecules and function of antigen‐presenting cells via an IL‐10‐mediated mechanism

et al. 2006

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High-molecular-weight components (PI) of Ascaris suum suppress both cell-mediated and humoral responses against ovalbumin (OVA) via an IL-4/IL-10-dependent mechanism. The aim of this work was to investigate the effect of PI on the ability of APC to activate T cells and the role of IL-10 in this process. Flow cytometry analyses of MHC class II, CD80, CD86 and CD40 molecules on LN cells from mice immunized with OVA or OVA+PI showed that PI inhibits expression of these molecules on unfractionated cells and on purified CD11c + cells. A low proliferative response was obtained when OVA-specific TCR-Tg T cells were incubated with CD11c + cells from OVA+PI-immunized mice pulsed with OVA, when compared to those incubated with cells from OVAimmunized mice. Similar results were obtained using as APC CD11c + cells from OVAimmunized mice pulsed with OVA+PI, which also expressed less of the four markers. The inhibitory effect of PI on both the expression of costimulatory molecules and the induction of T cell proliferation was abolished in IL-10-deficient mice. Our data indicate that the potent immunosuppressive effect of A. suum extract components on the host immune system is primarily related to their property of down-regulating the Agpresenting ability of DC via an IL-10-mediated mechanism.

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CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells

Cited by 505 publications

References 9 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

Inhibitory Feedback Loop Between Tolerogenic Dendritic Cells and Regulatory T Cells in Transplant Tolerance

Immunosuppressive components of Ascaris suum down‐regulate expression of costimulatory molecules and function of antigen‐presenting cells via an IL‐10‐mediated mechanism

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