In vitro–expanded human CD4+CD25+ T-regulatory cells can markedly inhibit allogeneic dendritic cell–stimulated MLR cultures

Godfrey, Wayne R.; Ge, Ying; Spoden, Darrin J.; Levine, Bruce L.; June, Carl H.; Blazar, Bruce R.; Porter, Stephen

doi:10.1182/blood-2004-01-0151

Cited by 252 publications

(185 citation statements)

References 45 publications

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“…Our results show that allogeneic stimulation of naive T cells in the presence of RA consistently induced the de novo differentiation of Treg cells with an unbiased homing potential, presenting effective in vivo suppressive abilities in a skin allograft model. Several protocols have been developed to generate Treg cells; some are designed to produce polyclonal Treg cells by stimulating naive T cells with anti-CD3 in anti-inflammatory conditions [55,56], while others have expanded selected thymus-derived Treg cells [29,30]. Although these Treg cells can be used to produce tolerance to a transplanted tissue, they cannot be used for cellular therapy in humans due to the lack of specificity.…”

Section: Discussionmentioning

confidence: 99%

“…Among the protocols designed to obtain adequate numbers of Treg cells for use in immunotherapy, the polyclonal expansion of Thymus-derived Treg cells using anti-CD3/anti-CD28 beads plus IL-2 has been shown to be the most efficient method for ex vivo expansion of both mouse and human Treg cells [29][30][31][32]. However, the expansion of thymus derived Treg cells and the generation of polyclonal in vitro-induced Treg (iTreg) cells from naive cells have the disadvantage that these cells are expanded/generated from an existing pool, and have a broad rather than a selective reactivity towards alloantigens.…”

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…High doses of exogenous IL-2 are usually required for the generation of human polyclonal or antigen-specific CD4 1 Tregs in vitro, [10][11][12] although it has been reported that IL-2 from activated CD4 1 CD25 2 T cells could help the expansion of CD4 1 CD25 1 Tregs. 33 We did not detect IL-2 expression in CD4 1 T cells cocultured with either imDCs or CD40-B in our system (data not shown).…”

Section: Treg Induced By B Cells J Zheng Et Al 48mentioning

confidence: 99%

“…[9][10][11][12][13] However, the general suppression of recipients' immune systems caused by these polyclonal Tregs may impair normal host defense against infectious or harmful substances and lead to disastrous consequences. In contrast, antigenspecific Tregs are more efficient and able to prevent specific T-cellmediated inflammation without the global immune suppression induced by polyclonal Tregs.…”

mentioning

confidence: 99%

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

et al. 2010

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CD4 1 regulatory T cells (Tregs) play an important role in maintaining immune tolerance by suppressing pathologic immune responses. The generation of large numbers of antigen-specific Tregs ex vivo is critical for the development of clinical immunotherapy based on the adoptive transfer of Tregs. Both CD40-activated B cells (CD40-B) and immature dendritic cells (imDCs) have been used as professional antigen-presenting cells (APCs) to generate antigen-specific Tregs. However, the efficiencies of CD40-B and imDCs to generate CD4 1 Tregs have not been compared directly and the mechanism driving the generation of these Tregs remains largely unknown. In this study, we found that CD40-B exhibited mature phenotypes and were more able to induce and expand CD4 high CD25 1 Tregs than imDCs. Moreover, Tregs induced by CD40-B had greater suppressive capacity than those induced by imDCs. The generation of CD4 high CD25 1 Tregs by CD40-B and imDCs is cell-cell contact dependent and partially relies on the expression of human leukocyte antigen (HLA)-DR and CD80/86. Differences in CD4 high CD25 1 Treg generation efficiency were largely explained by the production of endogenous IL-2 by CD40-B. Our results suggest that CD40-B is better able to generate large numbers of antigen-specific Tregs than imDCs. Additionally, using CD40-B to generate Tregs may accelerate the clinical use of Treg-based immunotherapy in the treatment of allograft rejection, graft versus host disease (GVHD) and autoimmune diseases.

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“…Large-scale expansion of CD4 þ CD25 þ Tregs, up to 1000 times, using anti-CD3 and anti-CD28 microbeads and high doses of IL-2 has demonstrated the feasibility of bringing this new treatment modality to the bedside. 80,81 Indeed, several clinical trials using Tregs that have been ex vivo expanded by different methods have been initiated. 82 It is important to note, however, that the number of Tregs required for adequate control of GVHD may be much fewer compared to their need in other clinical settings given the overall lymphopenic condition of HCT patients.…”

Section: Future Directionsmentioning

confidence: 99%

Regulating regulatory T cells

Chao

2006

Bone Marrow Transplant

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In vitro–expanded human CD4+CD25+ T-regulatory cells can markedly inhibit allogeneic dendritic cell–stimulated MLR cultures

Cited by 252 publications

References 45 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

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

Regulating regulatory T cells

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