Tregs and transplantation tolerance

Walsh, Patrick; Taylor, Daniel D.; Turka, Laurence A.

doi:10.1172/jci200423238

Cited by 179 publications

(102 citation statements)

References 68 publications

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“…The rationale for combining CTLA-4Ig and MR1 has previously been reviewed (3,4). However, the exact mechanism underlying tolerance induction is still controversial, as both Treg activity and clonal deletion have been proposed to play a role (22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

“…Both naturally occurring (20) and adaptive Treg (21) have been demonstrated to play a role in the development of allotolerance (22,23), including that achieved by costimulation blockade (24). Ex vivo tolerance induction via costimulation blockade is abrogated when murine natural Treg (nTreg) are depleted from the responder cell population, as measured by intact responses to alloantigen restimulation in vitro and in vivo.…”

mentioning

confidence: 99%

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Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

Verbinnen

Billiau²,

Vermeiren

et al. 2008

The Journal of Immunology

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Blocking of costimulatory signals for T cell activation leads to tolerance in several transplantation models, but the underlying mechanisms are incompletely understood. We analyzed the involvement of regulatory T cells (Treg) and deletion of alloreactive cells in the induction and maintenance of tolerance after costimulation blockade in a mouse model of graft-vs-host reaction. Injection of splenocytes from the C57BL/6 parent strain into a sublethally irradiated F1 offspring (C57BL/6 × C3H) induced a GVHR characterized by severe pancytopenia. Treatment with anti-CD40L mAb and CTLA4-Ig every 3 days during 3 wk after splenocyte injection prevented disease development and induced a long-lasting state of stable mixed chimerism (>120 days). In parallel, host-specific tolerance was achieved as demonstrated by lack of host-directed alloreactivity of donor-type T cells in vitro and in vivo. Chimerism and tolerance were also obtained after CD25+ cell-depleted splenocyte transfer, showing that CD25+ natural Treg are not essential for tolerance induction. We further show that costimulation blockade results in enhanced Treg cell activity at early time points (days 6–30) after splenocyte transfer. This was demonstrated by the presence of a high percentage of Foxp3+ cells among donor CD4+ cells in the spleen of treated animals, and our finding that isolated donor-type T cells at an early time point (day 30) after splenocyte transfer displayed suppressive capacity in vitro. At later time points (>30 days after splenocyte transfer), clonal deletion of host-reactive T cells was found to be a major mechanism responsible for tolerance.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

Verbinnen

Billiau²,

Vermeiren

et al. 2008

The Journal of Immunology

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“…1 These novel T cells are composed of two major subpopulations, natural Tregs and induced Tregs, 1 and have been confirmed to play crucial roles in autoimmune diseases 1,2 and cancer. 3,4 In vitro and in vivo experiments have also suggested the therapeutic potential of Tregs to prevent and treat T-cell-mediated inflammatory diseases, such as promoting transplantation tolerance, 5,6 inhibiting graft versus host disease (GVHD) 7,8 and controlling autoimmune diseases. 2 However, the clinical application of nature Tregs, which are formed by negative selection in the thymus, 1 has been limited due to their low frequency (only 1-5% in peripheral blood CD4 1 T cells) and lack of antigen-specificity.…”

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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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“…R egulatory T cells (Treg) 3 offer considerable promise for adoptive immunotherapy of autoimmune diseases and allograft rejection (1)(2)(3)(4). Particular interest has focused on so-called naturally arising Treg, a population that appears to represent a unique lineage of T cells within the thymus and that shows potent suppressor activity and comparative abundance (6 -12% of the CD4 ϩ T cell population) (3,4).…”

mentioning

confidence: 99%

Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells

Raimondi¹,

Shufesky²,

Tokita³

et al. 2006

The Journal of Immunology

160

119

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More effective discrimination between CD4+CD25+ regulatory T cells (Treg) and activated T cells would significantly improve the current level of purification of Treg and their therapeutic application. We observed that ∼90% of Treg (positive for the nuclear transcription factor Forkhead winged helix protein-3 and able to inhibit naive T cell proliferation) isolated from the spleens or lymph nodes of normal mice did not express significant levels of the inhibitory receptor programmed cell death-1 (PD-1) on their surface, but retained PD-1 intracellularly. An identical phenotype was also identified for human CD4+CD25high T cells isolated from peripheral blood of healthy volunteers. By contrast, activated T cells expressed high levels of surface PD-1 that paralleled up-regulation of CD25 during effector cell expansion. This distinction allowed us to isolate CD4+CD25+PD-1− T cells with suppressive activity from mice immunized with mature allogeneic dendritic cells. Although purification was limited to resting Treg because TCR ligation induced up-regulation of surface PD-1, this strategy nevertheless represents a valuable step toward more definitive characterization of Treg and their improved purification for therapeutic assessment.

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Tregs and transplantation tolerance

Cited by 179 publications

References 68 publications

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

Contribution of Regulatory T Cells and Effector T Cell Deletion in Tolerance Induction by Costimulation Blockadel

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

Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells

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