Sensitization to self (virus) antigen by in situ expression of murine interferon-gamma.
Autoimmune disease results from inflammatory destruction of tissues by aberrant self-reactive lymphocytes. We studied the autoimmune potential of T lymphocytes immunologically ignorant of viral antigens acting as self antigens and whether the host defense molecule IFN-gamma could stimulate these cells to cytotoxic competency. For this purpose, we produced double transgenic mice expressing pancreatic IFN-gamma as well as lymphocytic choriomeningitis virus (LCMV) nucleoprotein (NP) or glycoprotein (GP) antigen. 100% of the NP+/IFN-gamma+ mice became diabetic before 2 mo of age, while none of the NP single transgenic littermates and only 10% of IFN-gamma single transgenic littermates did. Strikingly, NP+/IFN-gamma+ mice spontaneously developed cytotoxic T lymphocyte activity on LCMV-infected targets and vaccinia virus-NP-infected ones without prior LCMV infection but NP+/IFN-gamma- mice did not, which indicates specific sensitization to the viral antigen by IFN-gamma. These results suggest that lymphocytes ignorant of self antigens can be activated by IFN-gamma released after immunologic stimulation such as viral infection. This mechanism may account for the loss of apparent tolerance to self antigens in autoimmune diseases such as insulin-dependent diabetes mellitus.
Lee
M S
MS
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037.
von Herrath
M
M
Reiser
H
H
Oldstone
M B
MB
Sarvetnick
N
N
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation; D000956:Antigens, Viral / Q000096:biosynthesis*; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D007371:Interferon-gamma / Q000096:biosynthesis*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D016133:Polymerase Chain Reaction; D013997:Time Factors; D014764:Viral Proteins / Q000096:biosynthesis
D000914:Antibodies, Viral; D000956:Antigens, Viral; D001786:Blood Glucose; D017931:DNA Primers; D014764:Viral Proteins; D007371:Interferon-gamma