GITR Ligand–Mediated Local Expansion of Regulatory T Cells and Immune Privilege of Corneal Allografts

Hori, Junko; Taniguchi, Hiroko; Wang, Mingcong; Oshima, Masamichi; Azuma, Miyuki

doi:10.1167/iovs.09-4959

Cited by 45 publications

(52 citation statements)

References 49 publications

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“…Additionally, because blockade of PD-1 ligands only partially reduced the ability of rapa-ECs to preferentially activate Tregs, it is likely that there are other mechanisms behind this observation. Although ligation of GITR on Tregs by GITR ligand was initially thought to abrogate their suppressive activity (78), recent studies suggest that GITR ligand may act to maintain and expand Tregs (79)(80)(81). Additionally, the interaction between OX40 and OX40 ligand has been shown to be important in Treg cell development in the gut (82), and an OX40 agonist enhanced Treg proliferation (83).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells

Wang¹,

Yi²,

Qin³

et al. 2013

J. Clin. Invest.

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Human graft endothelial cells (ECs) can act as antigen-presenting cells to initiate allograft rejection by host memory T cells. Rapamycin, an mTOR inhibitor used clinically to suppress T cell responses, also acts on DCs, rendering them tolerogenic. Here, we report the effects of rapamycin on EC alloimmunogenicity. Compared with mock-treated cells, rapamycin-pretreated human ECs (rapa-ECs) stimulated less proliferation and cytokine secretion from allogeneic CD4 + memory cells, an effect mimicked by shRNA knockdown of mTOR or raptor in ECs. The effects of rapamycin persisted for several days and were linked to upregulation of the inhibitory molecules PD-L1 and PD-L2 on rapa-ECs. Additionally, rapa-ECs produced lower levels of the inflammatory cytokine IL-6. CD4 + memory cells activated by allogeneic rapa-ECs became hyporesponsive to restimulation in an alloantigen-specific manner and contained higher percentages of suppressive CD4 + CD25 hi CD127 lo FoxP3 + cells that did not produce effector cytokines. In a human-mouse chimeric model of allograft rejection, rapamycin pretreatment of human arterial allografts increased graft EC expression of PD-L1 and PD-L2 and reduced subsequent infiltration of allogeneic effector T cells into the artery intima and intimal expansion. Preoperative conditioning of allograft ECs with rapamycin could potentially reduce immune-mediated rejection.

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Section: Discussionmentioning

confidence: 99%

Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells

Wang¹,

Yi²,

Qin³

et al. 2013

J. Clin. Invest.

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“…A third possibility is that allo-activated T-cells were being restrained by active immunoregulatory mechanisms and/or the inherent immune regulatory environment of the anterior chamber of the eye. The involvement of Foxp3 þ regulatory T-cells in graft acceptance has been documented in mice, 32 and availability of antibodies specific for both swine CD25, 33 and Foxp3 34 permit this to be investigated in pigs in future.…”

Section: Discussionmentioning

confidence: 99%

A Model of Corneal Graft Rejection in Semi-Inbred NIH Miniature Swine: Significant T-Cell Infiltration of Clinically Accepted Allografts

Nicholls¹,

Mitchard

Laycock

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…44 We have also found that constitutive expression of glucocorticoid-induced tumor necrosis factor receptor familyrelated protein ligand in the cornea mediates local expansion of CD25 + CD4 + T regulatory cells in the cornea and suppresses conventional effector T-cell function. 45 Thus, corneal tissue has a self-regulation system for preventing inflammationmediated corneal tissue destruction, using differently functioning molecules. These immune suppressive molecules are mainly expressed on corneal endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Immune Suppressive Microenvironment in the Cornea

Hori¹

2009

Cornea

Self Cite

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The eye, along with the brain and reproductive organs, possesses inherent immune privilege; therein, inflammation is selfregulated so as to preserve organ function. At present, 3 major mechanisms of immune privilege in the eye are thought to exist. These are: (1) anatomical, cellular, and molecular barriers in the eye; (2) eye-derived immunological tolerance known as anterior chamber-associated immune deviation; and (3) immune suppressive intraocular microenvironment. In this review, the mechanisms of immune privilege that have been learned from animal models of corneal transplantation are described. Also, the role of new B7 family molecule inducing T-cell apoptosis is discussed as a mechanism of local immune suppressive microenvironment in the cornea.

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GITR Ligand–Mediated Local Expansion of Regulatory T Cells and Immune Privilege of Corneal Allografts

Abstract: Presence of Foxp3+CD25+CD4(+) Treg in the allograft is necessary for allograft survival. GITRL-dependent expansion of Treg within the cornea is one mechanism underlying immune privilege in corneal allografts.

Cited by 45 publications

References 49 publications

Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells

Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells

A Model of Corneal Graft Rejection in Semi-Inbred NIH Miniature Swine: Significant T-Cell Infiltration of Clinically Accepted Allografts

Molecular Mechanisms of Immune Suppressive Microenvironment in the Cornea

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