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 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.