Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia

Trenado, Aurélie; Charlotte, Frédéric; Fisson, Sylvain; Yagello, Micaël; Klatzmann, David; Salomon, Benoı̂t L.; Cohen, José L.

doi:10.1172/jci17702

Cited by 437 publications

(316 citation statements)

References 40 publications

(30 reference statements)

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“…Clearly, the potential beneficial effects of TReg are both to limit unwanted clonal expansion and to control autoimmunity. A potential harmful effect of such cells is that they may prevent antitumor immune responses (54). In the mammalian adaptive immune system, apparently a delicate balance exists between the presence or absence of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-Tα Gene-Deleted Mouse

Bosco

Agenès

Rolink

et al. 2006

The Journal of Immunology

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In pre-Tα (pTα) gene-deleted mice, the positively selectable CD4+CD8+ double-positive thymocyte pool is only 1% that in wild-type mice. Consequently, their peripheral T cell compartment is severely lymphopenic with a concomitant increase in proportion of CD25+FoxP3+ regulatory T cells. Using mixed bone marrow chimeras, where thymic output was 1% normal, the pTα−/− peripheral T cell phenotype could be reproduced with normal cells. In the pTα−/− thymus and peripheral lymphoid organs, FoxP3+CD4+ cells were enriched. Parabiosis experiments showed that many pTα−/−CD4+ single-positive thymocytes represented recirculating peripheral T cells. Therefore, the enrichment of FoxP3+CD4+ single-positive thymocytes was not solely due to increased thymic production. Thus, the pTα−/− mouse serves as a model system with which to study the consequences of chronic decreased thymic T cell production on the physiology of the peripheral T cell compartment.

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Section: Discussionmentioning

confidence: 99%

Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-Tα Gene-Deleted Mouse

Bosco

Agenès

Rolink

et al. 2006

The Journal of Immunology

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“…Recent advances have demonstrated that adoptively transferred exogenous Treg can inhibit graft versus host disease (GVHD) [1][2][3]. However, the availability of sufficient numbers of donor Treg for cell-based therapies remains limited [4].…”

Section: Introductionmentioning

confidence: 99%

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

et al. 2009

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Induced antigen-specific Foxp3 1 T cells (iTreg) are being discussed as a promising alternative to polyclonal natural Foxp3 1 T cells (nTreg) for cell-based therapies, particularly to achieve transplantation tolerance. Using Foxp3eGFP-reporter mice, we here establish an efficient protocol to induce and expand alloantigen-specific iTreg from Foxp3 À CD4 1 T cells with cluster-disrupted DC. These iTreg were mainly CD62L 1 and showed efficient suppressive activity in vitro. However, in contrast to nTreg, adoptively transferred iTreg entirely failed to prevent lethal graft versus host disease (GVHD). Within irradiated recipients, the majority of adoptively transferred Foxp3 1 iTreg, but not Foxp3 1 nTreg quickly reverted to Foxp3 À CD4 1 T cells. We therefore suggest that therapeutic approaches to treat GVHD should rely on nTreg, whereas the use of de novo alloantigen-induced iTreg should be handled with caution since the stability of the regulatory phenotype of the iTreg could be of major concern.Key words: Animal models . Dendritic cells . Graft rejection . Regulatory T cells See accompanying article by commentary by Edinger IntroductionRecent advances have demonstrated that adoptively transferred exogenous Treg can inhibit graft versus host disease (GVHD) [1][2][3]. However, the availability of sufficient numbers of donor Treg for cell-based therapies remains limited [4]. Besides the in vitro expansion of nTreg [5], an obvious approach to solve this problem would be the de novo induction and expansion of Foxp3 1 Treg from abundant naïve CD4 1 T cells with recipient alloantigens [6,7]. Instead of mediating unspecific suppression, such alloantigen-induced Treg potentially could provide the advantage of antigen-specific regulation, thereby reducing the risk of disease relapse and infections [8]. Here, we present an efficient protocol to induce Foxp3 1 Treg by the use of clusterdisrupted allogeneic DC. Such allo DC-induced iTreg were functionally active in vitro and displayed a stable regulatory phenotype upon adoptive transfer into untreated syngeneic recipients. However, when used in experimental acute GVHD, these cells quickly lost Foxp3 expression and, in contrast to nTreg, did not show any protective effect. SHORT COMMUNICATION Results and discussionTo define conditions suited for the de novo induction of alloantigen-specific iTreg, we isolated Foxp3 À CD4 1 T cells from C57BL/6 Foxp3EGFP mice and co-cultured them with BM-derived allogeneic BALB/c DC that were either matured by application of LPS or via ''cluster-disruption'' (CD-DC). Disruption of the Ecadherin-mediated cell-cell contacts induces DC maturation through mechanisms distinct from TLR signaling [9]. Since antigen-loaded CD-DC have been shown to induce tolerance in mice after i.v. injection [9] we established a protocol that allowed the conversion of naïve to Foxp3 expressing cells in vitro in the presence of allogeneic but not syngeneic CD-DC. When compared with LPS-matured DC, CD-DC showed equally high expression of MHC class II, but diminished up...

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“…70 In contrast, simultaneous adoptive transfer of Tregs and unselected donor T-cells in mismatched mouse transplant models showed protection from GvHD without impairing tumor control. 71,72 It has been suggested that this apparent specificity of Tregs for alloreactive T-cells rather than tumor-reactive T-cells may relate to a different mechanism for the development of GvHD and GVL effect. GvHD may predominantly occur owing to alloantigen-driven expansion of alloreactive T-cells, whereas GVL effect may rely predominantly on activation of alloreactive T-cells.…”

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confidence: 99%

Umbilical cord blood graft engineering: challenges and opportunities

Thompson

Rezvani

Hosing

et al. 2015

Bone Marrow Transplant

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We are entering a very exciting era in umbilical cord blood transplantation (UCBT), where many of the associated formidable challenges may become treatable by ex vivo graft manipulation and/or adoptive immunotherapy utilizing specific cellular products. We envisage the use of double UCBT rather than single UCBT for most patients; this allows for greater ability to treat larger patients as well as to manipulate the graft. Ex vivo expansion and/or fucosylation of one cord will achieve more rapid engraftment, minimize the period of neutropenia and also give certainty that the other cord will provide long-term engraftment/immune reconstitution. The non-expanded (and future dominant) cord could be chosen for characteristics such as better HLA matching to minimize GvHD, or larger cell counts to enable part of the unit to be utilized for the development of specific cellular therapies such as the production of virus-specificT-cells or chimeric-antigen receptor T-cells which are reviewed in this study.

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Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia

Cited by 437 publications

References 40 publications

Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-Tα Gene-Deleted Mouse

Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-Tα Gene-Deleted Mouse

Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD

Umbilical cord blood graft engineering: challenges and opportunities

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Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia

Cited by 437 publications

References 40 publications

Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-Tα Gene-Deleted Mouse

Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-Tα Gene-Deleted Mouse

Alloantigen‐specific de novo‐induced Foxp3+ Treg revert in vivo and do not protect from experimental GVHD

Umbilical cord blood graft engineering: challenges and opportunities

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Alloantigen‐specific de novo‐induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD