HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shen, L. Articles by Dana, M. R. Search for Related Content PubMed PubMed Citation Articles by Shen, L. Articles by Dana, M. R.

The Function of Donor versus Recipient Programmed Death-Ligand 1 in Corneal Allograft Survival¹

Linling Shen^*, Yiping Jin^*, Gordon J. Freeman, Arlene H. Sharpe and M. Reza Dana^2,*

^* Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114; and Department of Medical Oncology, Dana-Farber Cancer Institute, and Departments of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115

Programmed death-ligand (PD-L)1 and PD-L2, newer B7 superfamily members, are implicated in the negative regulation of immune responses and peripheral tolerance. To examine their function in alloimmunity, we used the murine model of orthotopic corneal transplantation. We demonstrate that PD-L1, but not PD-L2, is constitutively expressed at high levels by the corneal epithelial cells, and at low levels by corneal CD45⁺ cells in the stroma, whereas it is undetectable on stromal fibroblasts and corneal endothelial cells. Inflammation induces PD-L1 up-regulation by corneal epithelial cells, and infiltration of significant numbers of PD-L1⁺CD45⁺CD11b⁺ cells. Blockade with anti-PD-L1 mAb dramatically enhances rejection of C57BL/6 corneal allografts by BALB/c recipients. To examine the selective contribution of donor vs host PD-L1 in modulating allorejection, we used PD-L1^–/– mice as hosts or donors of combined MHC and minor H-mismatched corneal grafts. BALB/c grafts placed in PD-L1^–/– C57BL/6 hosts resulted in pronounced T cell priming in the draining lymph nodes, and universally underwent rapid rejection. Allografts from PD-L1^–/– C57BL/6 donors were also significantly more susceptible to rejection than wild-type C57BL/6 grafts placed into BALB/c hosts, primarily as a result of increased T cell infiltration rather than enhanced priming. Taken together, our results identify differential roles for recipient vs donor PD-L1 in regulating induction vs effector of alloimmunity in corneal grafts, the most common form of tissue transplantation, and highlight the importance of peripheral tissue-derived PD-L1 in down-regulating local immune responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01-EY12963, P20 RR20753, AI56299, and AI39671.

² Address correspondence and reprint requests to Dr. M. Reza Dana, Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114. E-mail address: Reza.dana{at}schepens.harvard.edu

³ Abbreviations used in this paper: PD-L, programmed death-ligand; BM, bone marrow.

This article has been cited by other articles:

				J. A. Lucas, J. Menke, W. A. Rabacal, F. J. Schoen, A. H. Sharpe, and V. R. Kelley Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice J. Immunol., August 15, 2008; 181(4): 2513 - 2521. [Abstract] [Full Text] [PDF]