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 Syndrome

Zheng, Song Guo; Wang, Ju Hua; Koss, Michael N.; Quismorio, Francisco P.; Gray, J. Dixon; Horwitz, David A.

doi:10.4049/jimmunol.172.3.1531

Cited by 214 publications

(174 citation statements)

References 42 publications

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“…Introduction of Treg cell-depleted parental cells induced significantly lower levels of anti-DNA IgG1 in the recipient than did introduction of total parental cells (Figure 1). This result was surprising, because alloantigen-specific Treg cells have been shown to be able to inhibit cGVHD (Zheng et al, 2004;Kim et al, 2005). In these cases, it is thought that a large number of Treg cells can inhibit the activity of alloantigen-specific CD4 + T cells that are prerequisite for breaking self-tolerance of B cells.…”

Section: Resultsmentioning

confidence: 75%

“…Even though it is well known that Treg cells can prevent both aGVHD (Hoffman et al, 2002;Taylor et al, 2002;Edinger et al, 2003) and cGVHD (Zheng et al, 2004;Kim et al, 2005), little is known regarding their involvement in the pathogenesis of cGVHD versus aGVHD. In human cGVHD, there is evidence showing that Treg cells are positively associated with cGVHD (Clark et al, 2004), although contradictory data have been reported more recently (Miura et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…It seems that the size of Treg cells is important. Because infusion of a large number of Treg cells cultured in vitro can inhibit the production of autoantibody in cGVHD that can't occur without the help of CD4 + T cells (Zheng et al, 2004;Kim et al, 2005), it is possible that the infused Treg cells can inhibit the activity of CD4 + T cells as well as CD8 + T cells. From these observations, it may be inferred that there is a hierarchy of T-cell subsets in the susceptibility to the suppressive activity of Treg cells.…”

Section: Discussionmentioning

confidence: 99%

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Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

Kim

Kim²,

Choi³

et al. 2006

Exp Mol Med

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In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8 + T cells rapidly fall into anergy to host cells, while donor CD4 + T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8 + T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8 + T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4 + CD25 + regulatory T cells (T reg cells) are critical in maintaining the donor CD8 + T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of T reg cells in determining cGVHD versus aGVHD.

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Section: Resultsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

Kim

Kim²,

Choi³

et al. 2006

Exp Mol Med

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“…Treg cells can indeed be expanded ex vivo with allogeneic B cells [70] and these express very high levels of FoxP3, maintain an anergic phenotype, and are potent suppressors capable of inhibiting activated T cell responses [70]. Several previous studies have indeed demonstrated that the adoptive transfer of iTregs can suppress disease development in a lupus syndrome-like model [72,73], experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis [74], an autoimmune gastritis model [75][76], spontaneous development of type 1 diabetes in mice [77], Th1-mediated colitis [78], Th17-mediated diseases [79], and house dust mite-induced allergic pathogenesis in an asthmatic mouse model [80].…”

Section: Adoptive Transfer Therapy Using Regulatory T Cellsmentioning

confidence: 99%

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Dwivedi

Kemp

Laddha

et al. 2015

Autoimmunity Reviews

103

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Vitiligo is a hypomelanotic autoimmune skin disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses against melanocytes.Regulatory T cells (Tregs) are crucial to the development of self-tolerance and so are major foci in the study of autoimmune pathogenesis of vitiligo. This review will summarise recent findings concerning the role of Tregs in the pathogenesis of vitiligo. In addition, as antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, new strategies that expand or induce de novo generation of Tregs and which are currently being investigated as therapies for other autoimmune diseases, will be discussed. These approaches will highlight the opportunities for Treg cell-based therapeutics in vitiligo.4

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“…In addition to the different CD4 + Treg that have been described, there are reports suggesting that the CD8 + T cell compartment also contains cells with regulatory properties [15][16][17][18][19][20][21]. A report in the present issue of the European Journal of Immunology by Maile et al [22] describes the identification of CD8 + Treg that arise after stimulation with peptide-loaded MHC class I tetramers in vivo.…”

mentioning

confidence: 99%

Induced peripheral regulatory T cells: The family grows larger

Höglund

2006

Eur J Immunol

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In order to control immune reactions and to prevent autoimmunity, the immune system relies on a multitude of regulatory T cells (Treg). Most work in this field has focussed on Treg of the CD4 + T cell subset because of the central role CD4 + T cells play as initiators and regulators of immune responses. One discovery of particular importance was the identification of naturally occurring CD4 + CD25 + Treg that arise in the thymus and express the transcription factor Foxp3; however, Treg can also be induced in the periphery after immune activation. A paper in this issue of the European Journal of Immunology identifies a novel type of induced murine CD8 + Treg that arise in TCR HY transgenic female mice after injection of MHC class I tetramers loaded with HY peptide. These Treg prevent subsequent rejection of male skin grafts suggesting that their manipulation may represent a new way of improving graft rejections against minor histocompatibility barriers. Humans have developed two principally different mechanisms to secure self tolerance: thymic negative selection and extrathymic control by specialized T cells with potential regulatory capacity. In the first process, developing T cell precursors that happen to express an autoreactive TCR are deleted. Thymic negative selection is also surprisingly efficient against tissue-specific antigens. The reason for this is the presence of a unique transcription factor, autoimmune regulator (AIRE), that operates in rare antigen-presenting cells in the thymic medulla [1]. AIRE liberates expression of tissue-specific antigens and, in this way, allows negative selection of autoreactive thymocytes. The importance of the AIRE gene for negative selection is illustrated by the large range of autoimmune manifestations that result from a lack of AIRE function [2,3].Even if negative selection operates normally, autoreactive T cells nevertheless escape from the thymus, circulate in the blood and seed the peripheral lymphoid organs; however, while autoreactive T cells can be detected in all individuals upon in vitro re-stimulation, not all people develop autoimmune diseases. One reason for this is the existence of peripheral tolerance mechanisms that keep autoreactive cells in check. Of these, so called "regulatory T cells" (Treg) attract much attention. The most studied Treg is the CD4 + CD25 + cell, also called naturally arising regulatory T cells [4]. These cells originate in the thymus and are identified by the activity of the transcription factor Foxp3 [5]. CD4 + CD25 + Foxp3 + Treg exit from the mouse thymus

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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 Syndrome

Cited by 214 publications

References 42 publications

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Induced peripheral regulatory T cells: The family grows larger

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