Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes
Marc S. Horwitz, … , Enrique Rodriguez, Nora Sarvetnick
Marc S. Horwitz, … , Enrique Rodriguez, Nora Sarvetnick
Published January 1, 2002
Citation Information: J Clin Invest. 2002;109(1):79-87. https://doi.org/10.1172/JCI11198.
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Article

Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes

Abstract

The induction of autoimmunity by viruses has been attributed to numerous mechanisms. In mice, coxsackievirus B4 (CB4) induces insulin-dependent diabetes mellitus (IDDM) resembling the final step of disease progression in humans. The immune response following the viral insult clearly precipitates IDDM. However, the molecular pathway between viral infection and the subsequent activation of T cells specific for islet antigen has not been elucidated. These T cells could become activated through exposure to sequestered antigens released by damaged β cells, or they could have responded to factors secreted by the inflammatory response itself. To distinguish between these possibilities, we treated mice harboring a diabetogenic T cell repertoire with either the islet-damaging agent streptozotocin (STZ) or poly I:C, which nonspecifically activates T cells. Significantly, only treatment of mice with STZ resulted in IDDM and mimicked the effects observed following CB4 infection. Furthermore, antigen-presenting cells from STZ-treated mice were shown to directly activate autoreactive T cells and induce diabetes. Therefore, the primary role of CB4 in the precipitation of IDDM is to damage tissue, causing release and presentation of sequestered islet antigen. These events stimulate autoreactive T cells and thereby initiate disease.

Authors

Marc S. Horwitz, Alex Ilic, Cody Fine, Enrique Rodriguez, Nora Sarvetnick

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(a) Incidence of diabetes in BDC2.5 mice following poly I:C treatment. B...
(a) Incidence of diabetes in BDC2.5 mice following poly I:C treatment. BDC Tg mice and nontransgenic littermate controls were treated with 100 μg of poly I:C. Alternatively, BDC Tg mice were infected with 100 pfu of CB4. Mice were monitored twice weekly for blood glucose, and mice with two consecutive values over 300 mg/dl were considered diabetic. Both BDC2.5 mice (n = 12) and their nontransgenic littermates (n = 12) were analyzed and compared with untreated BDC Tg mice (n = 20). (b) Incidence of diabetes in BDC2.5 mice following STZ treatment. BDC Tg mice and nontransgenic littermates were treated with single doses of 0, 40, 80, or 160 mg/kg of STZ. Mice were monitored twice weekly for blood glucose, and mice with two consecutive values over 300 mg/dl were considered diabetic. (c) Incidence of diabetes in NOD/Shi mice following STZ treatment. Twelve-week-old NOD/Shi mice (n = 29) were treated with 80 mg/kg of STZ. Mice were monitored twice weekly for blood glucose, and mice with two consecutive values over 300 mg/dl were considered diabetic. Treated mice were analyzed and compared with untreated NOD/Shi mice (n = 10). Mice from all groups were age matched. Groups from b and c were compared for statistical significance by standard χ-square tests. Of the relevant comparisons, significant differences were observed between STZ-treated (80 mg/kg) BDC mice and STZ-treated (80 mg/kg) NOD mice at both 2 (P < 0.001) and 4 (P < 0.001) weeks after treatment.