Adenovirus E3 MHC inhibitory genes but not TNF/Fas apoptotic inhibitory genes expressed in beta cells prevent autoimmune diabetes.
To mimic events and molecules involved in type 1 insulin-dependent diabetes mellitus (T1D), we previously designed a transgenic (tg) mouse model where the viral nucleoprotein (NP) gene of lymphocytic choriomeningitis virus (LCMV) was expressed in the thymus to delete high affinity antiself (virus) T cells and in insulin-producing beta cells of the islets of Langerhans. Such tg mice, termed RIP-LCMV, fail to spontaneously develop diabetes. In contrast, when these mice are challenged with LCMV, they develop diabetes as they display hyperglycemia, low to absent levels of pancreatic insulin, and abundant mononuclear cell infiltrates in the islets. However, expressing the adenovirus early region (E3) gene in beta cells along with the LCMV transgene aborted the T1D. The present study utilizes this combined tg model (RIP LCMV x RIP E3) to define the requirement(s) of either pro-apoptotic TNF and Fas pathways or MHC class I up-regulation on beta cells for virus-induced T1D. Inhibitors to either pathway (TNF/Fas or MHC class I) are encoded in the E3 gene complex. To accomplish this task either the E3 region encoding the inhibitors of TNF and Fas pathways or the region encoding gp-19, a protein that inhibits transport of MHC class I molecules out of the endoplasmic reticulum were deleted in the RIP LCMV x RIP E3 model. Thus only the gp-19 is required to abort the virus-induced T1D. In contrast, removal of TNF- and Fas-pathway inhibitory genes had no effect on E3-mediated prevention of T1D.
Horwitz
Marshall S
MS
Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Efrat
Shimon
S
Christen
Urs
U
von Herrath
Matthias G
MG
Oldstone
Michael B A
MB
D017503:Adenovirus E3 Proteins / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000821:virology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology / Q000821:virology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
D017503:Adenovirus E3 Proteins; D015395:Histocompatibility Antigens Class I; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor