Galectin-9-Mediated Protection from Allo-Specific T Cells as a Mechanism of Immune Privilege of Corneal Allografts

Machiko Shimmura-Tomita,Hiroko Taniguchi,Mingcong Wang,Hisaya Akiba,Junko Hori,Hideo Yagita

doi:10.1371/journal.pone.0063620

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.

Highlights

Corneal transplantation is the most successful solid organ transplant in humans [1,2,3]
Expression of Gal-9 and T-cell immunoglobulin and mucin domain (Tim)-3 in normal mouse eyes Gal-9 mRNA was strongly expressed in freshly isolated cornea, iris-ciliary body, and the neural retina according to RT-PCR (Fig. 1A)
The present study has investigated whether Tim-3 and its ligand Gal-9 are involved in the immune-privileged status of the eye using the corneal allo-transplantation model and explored potential underlying mechanisms

Summary

Introduction

Corneal transplantation is the most successful solid organ transplant in humans [1,2,3]. The anterior chamber contains biologically relevant concentrations of various immunomodulatory neuropeptides, growth factors, cytokines, and soluble cell surface receptors, such as alpha-melanocyte-stimulating hormone [11], vasoactive intestinal peptide [12], calcitonin gene-related peptide [13], transforming growth factor (TGF)-b [14], thrombospondin [15], macrophage migration inhibitory factor [16], interleukin (IL)-1 receptor antagonist [17], CD46 [18], CD55 [18], CD59 [18], and CD95L [19] These factors suppress innate and adaptive immunity and maintain the immunosuppressive microenvironment within the eye [11,12,13,15,16,17,18,19]

Methods

Results

Conclusion