Neuronal programmed cell death-1 ligand expression regulates retinal ganglion cell number in neonatal and adult mice.
OBJECTIVE
During mouse retina maturation, the final number of retinal ganglion cells (RGCs) is determined by highly regulated programmed cell death. Previous studies demonstrated that the immunoregulatory receptor programmed cell death-1 (PD-1) promotes developmental RGC death. To identify the functional signaling partner(s) for PD-1, we identified retinal expression of PD-1 ligands and examined the effect of PD-1 ligand expression on RGC number. We also explored the hypothesis that PD-1 signaling promotes the development of functional visual circuitry.


METHODS
Characterization of retinal and brain programmed cell death-1 ligand 1 (PD-L1) expression were examined by immunofluorescence on tissue sections. The contribution of PD-ligands, PD-L1, and programmed cell death-1 ligand 2 (PD-L2) to RGC number was examined in PD-ligand knockout mice lacking 1 or both ligands. Retinal architecture was assessed by spectral-domain optical coherence tomography, and retinal function was analyzed by electroretinography in wild-type and PD-L1/L2 double-deficient mice.


RESULTS
PD-L1 expression is found throughout the neonatal retina and persists in adult RGCs, bipolar interneurons, and Müller glia. In the absence of both PD-ligands, there is a significant numerical increase in RGCs (34% at postnatal day 2 [P2] and 18% in adult), as compared to wild type, and PD-ligands have redundant function in this process. Despite the increased RGC number, adult PD-L1/L2 double-knockout mice have normal retinal architecture and outer retina function.


CONCLUSIONS
This study demonstrates that PD-L1 and PD-L2 together impact the final number of RGCs in adult mice and supports a novel role for active promotion of neuronal cell death through PD-1 receptor-ligand engagement.
Department of Pathology and Laboratory Medicine, Jules Stein Eye Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Caroline W
CW
Sham
Ann M
AM
Chan
Jacky M K
JM
Kwong
Joseph
J
Caprioli
Steven
S
Nusinowitz
Bryan
B
Chen
Janice G
JG
Lee
Nishant M
NM
Gandhi
Loise M
LM
Francisco
Arlene H
AH
Sharpe
Ling
L
Chen
Jonathan
J
Braun
Lynn K
LK
Gordon
D000375:Aging; D000818:Animals; D001369:Axons / Q000378:metabolism; D060890:B7-H1 Antigen / Q000172:deficiency / Q000378:metabolism*; D004596:Electroretinography; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009900:Optic Nerve / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000172:deficiency; D061026:Programmed Cell Death 1 Receptor / Q000172:deficiency; D012160:Retina / Q000166:cytology*; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D013057:Spectrum Analysis
D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor