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Infections That Induce Autoimmune Diabetes in BBDR Rats Modulate CD4⁺CD25⁺ T Cell Populations^1,2

Danny Zipris, Jan-Luuk Hillebrands^¶, Raymond M. Welsh^*,, Jan Rozing^¶, Jenny X. Xie, John P. Mordes, Dale L. Greiner^*, and Aldo A. Rossini^3,*,,

Programs in ^* Immunology and Virology and Molecular Medicine and Departments of Medicine and Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and ^¶ Division of Cell Biology, Section of Immunology, Faculty of Medical Sciences, University of Groningen, Groningen, The Netherlands

Viruses are believed to contribute to the pathogenesis of autoimmune type 1A diabetes in humans. This pathogenic process can be modeled in the BBDR rat, which develops pancreatic insulitis and type 1A-like diabetes after infection with Kilham’s rat virus (RV). The mechanism is unknown, but does not involve infection of the pancreatic islets. We first documented that RV infection of BBDR rats induces diabetes, whereas infection with its close homologue H-1 does not. Both viruses induced similar humoral and cellular immune responses in the host, but only RV also caused a decrease in splenic CD4⁺CD25⁺ T cells in both BBDR rats and normal WF rats. Surprisingly, RV infection increased CD4⁺CD25⁺ T cells in pancreatic lymph nodes of BBDR but not WF rats. This increase appeared to be due to the accumulation of nonproliferating CD4⁺CD25⁺ T cells. The results imply that the reduction in splenic CD4⁺CD25⁺ cells observed in RV-infected animals is virus specific, whereas the increase in pancreatic lymph node CD4⁺CD25⁺ cells is both virus and rat strain specific. The data suggest that RV but not H-1 infection alters T cell regulation in BBDR rats and permits the expression of autoimmune diabetes. More generally, the results suggest a mechanism that could link an underlying genetic predisposition to environmental perturbation and transform a "regulated predisposition" into autoimmune diabetes, namely, failure to maintain regulatory CD4⁺CD25⁺ T cell function.

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