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Originally published In Press as doi:10.1167/iovs.09-3602 on May 6, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:4941-4948.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3602
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Role of the Immune Modulator Programmed Cell Death-1 during Development and Apoptosis of Mouse Retinal Ganglion Cells

Ling Chen,1,2,3,4 Caroline W. Sham,3,5 Ann M. Chan,2 Loise M. Francisco,6,7 Yin Wu,6,7 Sergey Mareninov,2 Arlene H. Sharpe,6,7 Gordon J. Freeman,8,9 Xian-Jie Yang,2 Jonathan Braun,5 and Lynn K. Gordon2,10

1From the Departments of Molecular and Medical Pharmacology, 2Ophthalmology, Jules Stein Eye Institute, and 5Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; 6Departments of Pathology and 8Medicine, Harvard Medical School, Boston, Massachusetts; 7Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; 9Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and 10Ophthalmology Section, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California.

PURPOSE. Mammalian programmed cell death (PD)-1 is a membrane-associated receptor regulating the balance between T-cell activation, tolerance, and immunopathology; however, its role in neurons has not yet been defined. The hypothesis that PD-1 signaling actively promotes retinal ganglion cell (RGC) death within the developing mouse retina was investigated.

METHODS. Mature retinal cell types expressing PD-1 were identified by immunofluorescence staining of vertical retina sections; developmental expression was localized by immunostaining and quantified by Western blot analysis. PD-1 involvement in developmental RGC survival was assessed in vitro using retinal explants and in vivo using PD-1 knockout mice. PD-1 ligand gene expression was detected by RT-PCR.

RESULTS. PD-1 is expressed in most adult RGCs and undergoes dynamic upregulation during the early postnatal window of retinal cell maturation and physiological programmed cell death (PCD). In vitro blockade of PD-1 signaling during this time selectively increases the survival of RGCs. Furthermore, PD-1–deficient mice show a selective increase in RGC number in the neonatal retina at the peak of developmental RGC death. Lastly, gene expression of the immune PD-1 ligand genes Pdcd1lg1 and Pdcd1lg2 was found throughout postnatal retina maturation.

CONCLUSIONS. These findings collectively support a novel role for a PD-1–mediated signaling pathway in developmental PCD during postnatal RGC maturation.






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