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

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 costimulatory 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. (Am J Pathol 2008, 173:1682-1692, DOI: 10.2353/ajpath.2008.080314)