130 : Interplay between epigenetic mechanisms and signaling pathways will determine macrophage phenotypes in response to environmental cues

Abstract

An innate immune response clears herpes simplex virus type 1 (HSV-1) from the corneal epithelium following primary corneal infection. Herpetic epithelial keratitis is the most common form of HSV-1 corneal infection seen in the clinic, and can lead to an inflammatory sequel called herpes stromal keratitis that is the leading infectious cause of blindness in the United States. Interaction of the inhibitory receptor Programmed Death (PD)-1on inflammatory cells with its ligand (PD-L1/B7-H1) dampens adaptive immune responses, but its precise role in innate immune regulation is not fully understood. HSV-1 clearance from infected corneas was significantly enhanced in B7-H1 −/− mice compared to wild type mice as early as 1 day post infection (DPI), prior to the initial involvement of NK cells at 4 dpi. Normal corneas express PD-L1 on epithelial cells, and also possess resident CD45 + cells including dendritic cells and macrophages that might also express PD-L1. Fluorescence confocal microscopy revealed an increased number of infiltrating CD45 + cells, Gr-1 high cells, and CCR2 + cells in the central cornea of B7-H1 −/− mice at 1 DPI, in association with increased expression of the chemokines CCL2 by CD45 + cells in the central cornea, and CXCL2 by CD45 − cells around the viral lesion. Bone marrow chimera mice that expressed PD-L1/B7H1 only on bone marrow derived cells did not exhibit enhanced HSV-1 clearance until 4 DPI, at which time PD-L1 deficiency on parenchymal cells was associated with increased numbers of CD69 + and granzyme B + NK cells in the cornea. We conclude that PD-1 interaction with PD-L1 on hematopoetic cells suppresses effective viral clearance at 1 dpi by inhibiting local chemokine production and leukocytic infiltration, whereas the effect of PD-1 interaction with PD-L1 on non-hematopoetic cells (likely cornea epithelial cells) is delayed until 4 dpi and appears to involve inhibition of NK cell activation.