Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes
Marc S. Horwitz, Alex Ilic, Cody Fine, Enrique Rodriguez, Nora Sarvetnick
Marc S. Horwitz, Alex Ilic, Cody Fine, Enrique Rodriguez, Nora Sarvetnick
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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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Analysis of the activation state of lymphocytes from BDC2.5 mice followi...
Analysis of the activation state of lymphocytes from BDC2.5 mice following treatment with either poly I:C (a) or STZ (b). Cells were stained with antibody to Vβ4 TCR, CD4, and antibody to either CD25, CD44, or CD69. Cells were analyzed by FACS and compared to isotype controls. Shown are histograms of mean fluorescent intensities generated by gating on 10,000–20,000 CD4+, Vβ4+ cells, or Vβ4+, CD4– cells. (a). For both a and b, the plots are representative of one of six mice analyzed, and all six had similar results. (a) Analysis of peripheral blood lymphocytes before (narrow) and three days following poly I:C treatment (wide) from identical mouse are displayed. No shift of activation is observed in the Vβ4+, CD4+ T cell population while activation is observed in the Vβ4+, CD4– (CD8+) T cell population posttreatment (PT). Changes in cell populations and gated markers CD4+, Vβ4+: CD25, 5.7% to 7.2%; CD44-high, 28.6% to 25.2%; CD69, 6.7% to 6.9% and CD4–, Vβ4+: CD25, 2.9% to 27.8%; CD 44-high, 22.9% to 65.0%; CD69, 10.7% to 41.8%. (b) Analysis of lymphocytes from the spleen and pancreatic lymph node before (narrow) and seven days following STZ treatment (wide) are displayed. Mice were analyzed at three, five, and seven days PT. Similar results were observed at five days, but not at three days. A dramatic shift in all three activation markers was observed in the spleen PT. A less dramatic shift was observed in the pancreatic lymph node.Changes in cell populations and gated markers in spleen CD4+ Vβ4+ : CD25, 10.4% to 32.9%; CD44-high, 19.8% to 56.5%; CD69, 9.0% to 32.3%; and in pancreatic lymph nodes, CD4+ Vβ4+ : CD25, 5.4% to 25.3%; CD44-high, 7.2% to 18.9%; CD69, 8.7% to 27.0%.