Published online before print November 13, 2008

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(American Journal of Pathology. 2008;173:1682-1692.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080314

Increased Foxp3⁺ CD4⁺ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Jun Abe^*, Satoshi Ueha^*, Jun Suzuki^*, Yoshiaki Tokano, Kouji Matsushima^* and Sho Ishikawa^*

From the Department of Molecular Preventive Medicine,^* Graduate School of Medicine, University of Tokyo, Tokyo; and the Department of Rheumatology, School of Medicine, Juntendo University, Tokyo, Japan

Foxp3⁺ CD4⁺ regulatory T (T_reg) cells play a pivotal role in the maintenance of dominant self tolerance. Understanding how the failures of immune control by T_reg cells are involved in autoimmune diseases is important for the development of effective immunotherapies. In the present study, we analyzed the characteristics of endogenous T_reg cells in (NZB x NZW) F1 (BWF1) mice, a murine model of systemic lupus erythematosus. Unexpectedly, T_reg number and frequency in aged BWF1 mice with developing lupus nephritis were increased, not decreased, and in vitro suppressive activity in lymphoid organs was intact. In addition, T_reg cells trafficked to target organs because cells were present in the kidney and lung. T_reg cells of aged BWF1 mice exhibited altered localization within lymph organs, however, and an altered phenotype, with higher expression levels of chemokine receptors and activation markers, suggesting a highly activated cellular state. Notably, the expression levels of co-stimulatory molecules were also markedly enhanced in the T_reg cells of aged BWF1 mice. Furthermore, T_reg cells of BWF1 mice did not show any suppressive effects on antibody production in vitro. Taken together, we conclude that T_reg cells in BWF1 mice are not predisposed to functional incompetence but rather are present in a highly activated state.