Function of PD-1 in retinal development and ocular inflammation

Retinal ganglion cell (RGC) death is a critical step in the development of the mature retina and formation of effective neuronal networks. We hypothesize that active negative selection of neurons may be required in retinal maturation. Novel neuronal expression of certain canonical molecules of the immune system is functionally linked to neural differentiation and synaptic plasticity. Programmed cell death-1 (PD-1) is an important receptor molecule regulating cell-cell signaling and clonal fate in the immune system. The first part of this thesis addresses the involvement of PD-1 in intraocular inflammation. Expression of both PD-1 and its ligands was observed in inflammatory sites during active ocular inflammation suggesting a role for PD-1 interactions in the retinal microenvironment. Surprisingly, PD-1 was constitutively expressed in neurons of the naive mouse retina. The second part of this thesis addresses the function of PD-1 during retinal development. We report that PD-1 was expressed in most adult RGCs, and underwent dynamic upregulation during the window of postnatal retinal cell maturation and physiological programmed cell death. Blockade of PD-1 signaling in vitro results in an increased and selective survival of RGCs. PD-1 deficient mouse showed transiently increased retinal ganglion cells during postnatal retinal maturation. These findings suggest that the PD-1 mediated signaling pathway plays a novel role in the developmental programmed cell death during postnatal RGC maturation. Overall, this thesis will strengthen the concept of shared mechanisms of immune system and CNS, and shed light on the mechanism of physiological programmed cell death during CNS development, and enhance our understanding of the complex mechanisms contributing to neuronal cell death and survival in disease conditions.