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Galectin-9-mediated protection from allo-specific T cells as a mechanism of immune privilege of corneal allografts.

Shimmura-Tomita M, Wang M, Taniguchi H, Akiba H, Yagita H, Hori J - PLoS ONE (2013)

Bottom Line: The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation.T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand.Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Nippon Medical School, Tokyo, Japan. machiko@jichi.ac.jp

ABSTRACT
The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation. The immunosuppressive intraocular microenvironment is known as one of the mechanisms underlying immune privilege in the eye. T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand. We investigated the role of this pathway in establishing the immune-privileged status of corneal allografts in mice. Gal-9 is constitutively expressed on the corneal epithelium, endothelium and iris-ciliary body in normal mouse eyes and eyes bearing surviving allografts, and Tim-3 was expressed on CD8 T cells infiltrating the allografts. Allograft survival in recipients treated with anti-Tim-3 monoclonal antibody (mAb) or anti-Gal-9 mAb was significantly shorter than that in control recipients. In vitro, destruction of corneal endothelial cells by allo-reactive T cells was enhanced when the cornea was pretreated with anti-Gal-9 mAb. Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation. We propose that constitutive expression of Gal-9 plays an immunosuppressive role in corneal allografts. Gal-9 expressed on corneal endothelial cells protects them from destruction by allo-reactive T cells within the cornea.

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Blockade of Gal-9 or Tim-3 increases CD4 and CD8 T cell infiltration in allografts.Normal corneas of C57BL/6 mice were transplanted into normal eyes of BALB/c mice. All recipients were treated with anti-Tim-3 mAb, anti-Gal-9 mAb, or control rat IgG. Graft-bearing eyes were isolated at 4 weeks. (A, B, D, E, G, and H) Cryostat sections of graft-bearing eyes were examined by HE staining. (C, F, and I) Cryostat sections of graft-bearing eyes were examined by immunofluorescent staining with PE-conjugated anti-CD4 mAb (red) and FITC-conjugated anti-CD8 mAb (green). Nuclei were stained with DAPI (blue). Arrow heads in F and I show CD4+ cells and arrows in F and I show CD8+ cells. Original magnification, ×40. (J, K, L, and M) The number of CD4+ and CD8+ cells at graft center and host-graft junction in recipients treated with anti-Tim-3 mAb and anti-Gal-9 mAb was greater as compared to control recipients. Data are presented as the mean ± standard deviation of four corneas in each group.
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pone-0063620-g004: Blockade of Gal-9 or Tim-3 increases CD4 and CD8 T cell infiltration in allografts.Normal corneas of C57BL/6 mice were transplanted into normal eyes of BALB/c mice. All recipients were treated with anti-Tim-3 mAb, anti-Gal-9 mAb, or control rat IgG. Graft-bearing eyes were isolated at 4 weeks. (A, B, D, E, G, and H) Cryostat sections of graft-bearing eyes were examined by HE staining. (C, F, and I) Cryostat sections of graft-bearing eyes were examined by immunofluorescent staining with PE-conjugated anti-CD4 mAb (red) and FITC-conjugated anti-CD8 mAb (green). Nuclei were stained with DAPI (blue). Arrow heads in F and I show CD4+ cells and arrows in F and I show CD8+ cells. Original magnification, ×40. (J, K, L, and M) The number of CD4+ and CD8+ cells at graft center and host-graft junction in recipients treated with anti-Tim-3 mAb and anti-Gal-9 mAb was greater as compared to control recipients. Data are presented as the mean ± standard deviation of four corneas in each group.

Mentions: We next examined the graft-bearing eyes from anti-Gal-9 or anti-Tim-3 treated recipients at 4 weeks. HE staining showed that the number of infiltrating cells was increased by the anti-Gal-9 or anti-Tim-3 treatment at the graft center (Fig. 4A, D, G) as well as the host-graft junction (Fig. 4B, E, H). Immunofluorescent staining revealed that infiltration of both CD4+ T cells and CD8+ T cells was increased by the anti-Gal-9 or anti-Tim-3 treatment (Fig. 4C, F, I). The numbers of infiltrating CD4+ T cells and CD8+ T cells at graft center and host-graft junction were significantly increased in anti-Gal-9 or anti-Tim-3 treated recipients compared to control (Fig. 4J, K, L, M).


Galectin-9-mediated protection from allo-specific T cells as a mechanism of immune privilege of corneal allografts.

Shimmura-Tomita M, Wang M, Taniguchi H, Akiba H, Yagita H, Hori J - PLoS ONE (2013)

Blockade of Gal-9 or Tim-3 increases CD4 and CD8 T cell infiltration in allografts.Normal corneas of C57BL/6 mice were transplanted into normal eyes of BALB/c mice. All recipients were treated with anti-Tim-3 mAb, anti-Gal-9 mAb, or control rat IgG. Graft-bearing eyes were isolated at 4 weeks. (A, B, D, E, G, and H) Cryostat sections of graft-bearing eyes were examined by HE staining. (C, F, and I) Cryostat sections of graft-bearing eyes were examined by immunofluorescent staining with PE-conjugated anti-CD4 mAb (red) and FITC-conjugated anti-CD8 mAb (green). Nuclei were stained with DAPI (blue). Arrow heads in F and I show CD4+ cells and arrows in F and I show CD8+ cells. Original magnification, ×40. (J, K, L, and M) The number of CD4+ and CD8+ cells at graft center and host-graft junction in recipients treated with anti-Tim-3 mAb and anti-Gal-9 mAb was greater as compared to control recipients. Data are presented as the mean ± standard deviation of four corneas in each group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3646846&req=5

pone-0063620-g004: Blockade of Gal-9 or Tim-3 increases CD4 and CD8 T cell infiltration in allografts.Normal corneas of C57BL/6 mice were transplanted into normal eyes of BALB/c mice. All recipients were treated with anti-Tim-3 mAb, anti-Gal-9 mAb, or control rat IgG. Graft-bearing eyes were isolated at 4 weeks. (A, B, D, E, G, and H) Cryostat sections of graft-bearing eyes were examined by HE staining. (C, F, and I) Cryostat sections of graft-bearing eyes were examined by immunofluorescent staining with PE-conjugated anti-CD4 mAb (red) and FITC-conjugated anti-CD8 mAb (green). Nuclei were stained with DAPI (blue). Arrow heads in F and I show CD4+ cells and arrows in F and I show CD8+ cells. Original magnification, ×40. (J, K, L, and M) The number of CD4+ and CD8+ cells at graft center and host-graft junction in recipients treated with anti-Tim-3 mAb and anti-Gal-9 mAb was greater as compared to control recipients. Data are presented as the mean ± standard deviation of four corneas in each group.
Mentions: We next examined the graft-bearing eyes from anti-Gal-9 or anti-Tim-3 treated recipients at 4 weeks. HE staining showed that the number of infiltrating cells was increased by the anti-Gal-9 or anti-Tim-3 treatment at the graft center (Fig. 4A, D, G) as well as the host-graft junction (Fig. 4B, E, H). Immunofluorescent staining revealed that infiltration of both CD4+ T cells and CD8+ T cells was increased by the anti-Gal-9 or anti-Tim-3 treatment (Fig. 4C, F, I). The numbers of infiltrating CD4+ T cells and CD8+ T cells at graft center and host-graft junction were significantly increased in anti-Gal-9 or anti-Tim-3 treated recipients compared to control (Fig. 4J, K, L, M).

Bottom Line: The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation.T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand.Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Nippon Medical School, Tokyo, Japan. machiko@jichi.ac.jp

ABSTRACT
The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation. The immunosuppressive intraocular microenvironment is known as one of the mechanisms underlying immune privilege in the eye. T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand. We investigated the role of this pathway in establishing the immune-privileged status of corneal allografts in mice. Gal-9 is constitutively expressed on the corneal epithelium, endothelium and iris-ciliary body in normal mouse eyes and eyes bearing surviving allografts, and Tim-3 was expressed on CD8 T cells infiltrating the allografts. Allograft survival in recipients treated with anti-Tim-3 monoclonal antibody (mAb) or anti-Gal-9 mAb was significantly shorter than that in control recipients. In vitro, destruction of corneal endothelial cells by allo-reactive T cells was enhanced when the cornea was pretreated with anti-Gal-9 mAb. Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation. We propose that constitutive expression of Gal-9 plays an immunosuppressive role in corneal allografts. Gal-9 expressed on corneal endothelial cells protects them from destruction by allo-reactive T cells within the cornea.

Show MeSH
Related in: MedlinePlus