Enhanced clearance of herpes simplex virus type 1 and reduced herpetic eye disease in STAT6 knockout mice is associated with increased IL-2.
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(H)2-mediated immune response. Conversely, they have elevated levels of IL-2 and thus an increased T(H)1-mediated immune response. To assess the relative impact of reduced T(H)2- and elevated T(H)1-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.
Ghiasi
Homayon
H
Ophthalmology Research, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, CA 90048, USA. ghiasih@CSHS.Org
Osorio
Yanira
Y
Nesburn
Anthony B
AB
Wechsler
Steven L
SL
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001762:Blepharitis / Q000517:prevention & control; D005123:Eye / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D022283:Herpesvirus Vaccines / Q000008:administration & dosage / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000097:blood; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology*; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000517:prevention & control / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009500:Neutralization Tests; D050800:STAT6 Transcription Factor; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D014611:Vaccination
D000914:Antibodies, Viral; D022283:Herpesvirus Vaccines; D007132:Immunoglobulin Isotypes; D007376:Interleukin-2; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators