Enhanced Clearance of Herpes Simplex Virus Type 1 and Reduced Herpetic Eye Disease in STAT6 Knockout Mice Is Associated with Increased IL-2

Abstract

STAT6 (signal transducers and activators of transcription 6)-deficient (STAT6 −/−) mice have defects in IL-4- and IL-13-mediated functions and thus have a reduced T H2-mediated immune response. Conversely, they have elevated levels of IL-2 and thus an increased T H1-mediated immune response. To assess the relative impact of reduced T H2- and elevated T H1-dependent immune responses on HSV-1 infection, vaccinated and mock-vaccinated STAT6 −/− mice were challenged ocularly with HSV-1. Mock-vaccinated STAT6 −/− mice were as susceptible to lethal HSV-1 infection as parental BALB/c mice. Mock-vaccinated STAT6 −/− mice had reduced HSV-1 titers in their eyes compared to BALB/c mice. Furthermore, mock-vaccinated STAT6 −/− mice had significantly less corneal scarring than their BALB/c counterparts. Vaccination induced significantly higher serum-neutralizing antibody titers in STAT6 −/− mice compared to BALB/c mice, while completely protecting both types of mice against HSV-1-induced death and corneal scarring. Vaccinated STAT6 −/− mice had reduced HSV-1 titers in their eyes compared to BALB/c mice. Lymphocytes from both vaccinated and mock-vaccinated STAT6 −/− mice secreted higher amounts of IL-2 than lymphocytes from BALB/c mice, in the presence or absence of stimulation with UV-inactivated HSV-1. Finally, depletion of IL-2 increased ocular virus replication in STAT6 −/− mice to levels similar to that measured in BALB/c mice. Our results suggest that in the absence of the STAT6 pathway, IL-2-mediated immune responses are up-regulated. This, in turn, leads to faster viral clearance and, consequently, lower levels of eye disease.