Cornea-Infiltrating and Lymph Node Dendritic Cells Contribute to CD4+ T Cell Expansion after Herpes Simplex Virus-1 Ocular Infection

Abstract

Following herpes simplex virus type 1 (HSV-1) corneal infection, CD4+ T cells are expanded in the draining lymph nodes (DLN) and re-stimulated in the infected cornea to regulate the destructive inflammatory disease herpes stromal keratitis (HSK). The contribution of cornea resident, cornea infiltrating, and DLN resident dendritic cells (DC) to CD4+ T cell expansion in DLN and re-stimulation in corneas is unknown. Cornea resident and infiltrating DCs were selectively depleted by timed local (subconjunctival) injection of diphtheria toxin (DT) into mice that express high affinity DT receptors (DTR) from the CD11c promoter. Corneal and DLN DC were depleted by systemic (intraperitoneal) DT treatment. We found that: a) DC that were resident in the cornea and DLN at the time of infection or that migrate into the tissues during the first 24 h after infection were not required for CD4+ T cell expansion; b) DC that infiltrated the cornea > 24 h after infection were responsible for most of the CD4+ T cell expansion measured in the DLN at 3 and 7 days post infection (dpi); c) non cornea-derived DC that infiltrate the DLN > 24 h after infection made a modest contribution to CD4+ T cell expansion at 3 dpi, but did not contribute at 7 dpi; and d) surprisingly HSK development between 7–21 dpi did not require corneal DC. DC-independent HSK development appears to reflect close interactions of CD4+ T cells with MHC class II positive corneal epithelial cells and macrophages in infected DC-depleted corneas.

Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure

“…It is also interesting that in the corneas of IFN-␣␤␥R Ϫ/Ϫ ¡WT mice at 9 dpi, virus was not cleared. Consistent with our data, the cornea relies on both the resident and early infiltrating immune cell response for a proper response to HSV-1 (48,49). Our data add that the IFN competence of infiltrating immune cells is necessary for efficient viral clearance in this normally avascular site.…”

Loss of Neurokinin-1 Receptor Alters Ocular Surface Homeostasis and Promotes an Early Development of Herpes Stromal Keratitis

“…The infiltrating DCs can pick up the viral antigens and migrate to the draining lymph nodes (DLNs) to prime virus specific T cells (19). Therefore, we next ascertained the number of CD11c+ cells in DLNs of HSV-1 infected B6 and NK1R −/− mice at early time-points post-infection.…”

“…A recent study showed that CD4 T cell priming in DLNs of HSV-1 infected mice could be due to the drainage of soluble viral antigens from infected corneas or the migration of cornea-infiltrating DCs loaded with viral antigens to the DLNs (19). Our results showed an increased number of cDCs in infected corneas and the DLNs of NK1R −/− than B6 mice.…”

Cytokine Expression in Keratoconus and its Corneal Microenvironment: A Systematic Review

“…120 However, corneal epithelial cells are also able to express HLA class II molecules and present antigens directly to CD4+ T cells. 123 Histopathological examination of KC corneas reveals a moderate increase in the number of antigen-presenting cells compared to controls, but this increase is not as apparent as observed in inflamed corneas. 124 In …”