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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

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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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Figure 4

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Presentation of endogenous antigen by APCs from STZ-treated mice activat...
Presentation of endogenous antigen by APCs from STZ-treated mice activates β cell–specific BDC T cells. Adherent mononuclear cells from NOD mice treated with STZ or PBS were prepared, irradiated, and cultured with BDC2.5 Tg splenocytes (2 × 105) at various ratios. Shown is a summary of results from the 4:1 ratio, T cell (2 × 105): APC (5 × 104). Also shown are the results of culturing these cells at 4:1 in the presence of antigenic peptide (7 μM) (20) specific for the BDC T cell. Cultures were pulsed with 1 μCi of 3H thymidine at 48 hours and harvested 18 hours thereafter. The data presented are from four separate experiments involving a total of eight mice in each group representing the APC populations. Values are presented as stimulation index + SEM as compared with BDC splenocytes incubated without additional APCs or antigen. Background in all experiments was between 500 and 2500 cpm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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