The role of dendritic cells in the cornea in the adaptive immune response following Herpes Simplex Virus-1 ocular infection

Herpes simplex virus (HSV)-1 infection of the cornea results in expansion of CD4+ and CD8+ T cells in the draining lymph nodes (DLN), and causes a CD4+ T cell – mediated immunopathological disease in the cornea called herpes stromal keratitis (HSK). During steady state, the cornea possesses a resident population of CD11c+ CD11b- dendritic cells (cornea-resident DCs). CD11c+ DCs infiltrate the cornea after HSV-1 infection (cornea-infiltrating DCs), but their contribution to T cell expansion and the progression of HSK, as well as the role of DCs present in the DLN (DLN-resident DCs), following corneal infection is unknown. We employed mice that express high-affinity diphtheria toxin (DT) receptors from the CD11c promoter to selectively deplete CD11c+ dendritic cells present in the cornea and the DLN. We depleted cornea-resident and cornea-infiltrating DCs by timed local (subconjunctival) injection of DT into murine corneas. Corneal and DLN – derived DCs were depleted by systemic (intraperitoneal) DT treatment. The studies outlined in this thesis demonstrate the following: 1) DCs resident in the cornea and DLNs at the time of infection are not essential to CD4+ and CD8+ T cell expansion in the DLN, nor are they necessary for HSK development. 2) Cornea-infiltrating DCs are responsible for most of the CD8+ T cell expansion measured at 3 and 7 days post infection (dpi), and contribute to the prevention of lethal encephalitis. 3) Both cornea-infiltrating DCs and DLN – derived DCs participate in CD4+ T cell expansion at 3 dpi, with cornea-infiltrating DC stimulating CD4+ T cell expansion in the DLN at 7 dpi. Lastly, 4) although DCs infiltrate the cornea at the onset of disease, the development of HSK between 7 and 21 dpi did not require corneal DCs. In its place, associations of CD4+ T cells with MHC II – expressing corneal epithelial cells and macrophages may promote HSK progression in corneas depleted of DCs