Abstract
Rotavirus infection is associated with childhood progression to type 1 diabetes. Infection by monkey rotavirus RRV accelerates diabetes onset in non-obese diabetic (NOD) mice, which relates to regional lymph node infection and a T helper 1-specific immune response. When stimulated ex vivo with RRV, plasmacytoid dendritic cells (pDCs) from naïve NOD mice secrete type I interferon, which induces the activation of bystander lymphocytes, including islet-autoreactive T cells. This is our proposed mechanism for diabetes acceleration by rotaviruses. Here we demonstrate bystander lymphocyte activation in RRV-infected NOD mice, which showed pDC activation and strong upregulation of interferon-dependent gene expression, particularly within lymph nodes. The requirement for type I interferon signalling was analysed using NOD mice lacking a functional type I interferon receptor (NOD.IFNAR1−/− mice). Compared with NOD mice, NOD.IFNAR1−/− mice showed 8-fold higher RRV titers in lymph nodes and 3-fold higher titers of total RRV antibody in serum. However, RRV-infected NOD.IFNAR1−/− mice exhibited delayed pDC and lymphocyte activation, no T helper 1 bias in RRV-specific antibodies and unaltered diabetes onset when compared with uninfected controls. Thus, the type I interferon signalling induced by RRV infection is required for bystander lymphocyte activation and accelerated type 1 diabetes onset in genetically susceptible mice.
Highlights
Day post inoculation and secrete large amounts of type I interferons following activation, which are crucial to establish the anti-viral state and shape further innate and adaptive immune responses[13]
The pDC/cDC ratio is increased in diabetic patients over controls[21]. To determine whether this ratio is elevated in non-obese diabetic (NOD) mice in response to Rhesus monkey rotavirus (RRV) infection, pDCs and cDCs were identified by flow cytometry in individual RRV-infected NOD mice and their pDC/cDC ratios determined (Fig. 1a)
We show that RRV rotavirus infection of NOD mice strongly activates pDCs and induces type I interferon-dependent gene expression in mesenteric lymph nodes (MLN) and pancreatic lymph nodes (PLN)
Summary
Day post inoculation and secrete large amounts of type I interferons following activation, which are crucial to establish the anti-viral state and shape further innate and adaptive immune responses[13]. When stimulated ex vivo with RRV, NOD mouse-derived pDCs are sufficient to induce lymphocyte activation, including islet-specific CD8+ T cells[14] This bystander activation depends on signalling through the type I interferon receptor and Toll-like receptor 7, and is heightened in spleen cells from NOD mice over C57BL/6 mice[14]. PDC activation and type I interferon-mediated bystander activation may contribute to the diabetes acceleration in RRV-infected NOD mice. As NOD mice lacking a functional type I interferon receptor still progress to diabetes, type I IFN may be redundant for disease development[22]. We assessed DC activation following RRV infection and the dependence of diabetes acceleration on type I interferon receptor signalling. Without type I interferon receptor signalling, pDC and lymphocyte activation by RRV was delayed and diabetes development was unaltered. RRV acceleration of diabetes requires type I interferon-dependent responses
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