The intracellular expression of the programmed death receptor 1 (PD1) identifies a subset of naive T_reg cells with enhanced suppressive ability; antigen stimulation results in the surface expression of PD1. Because the role of T_reg impairments in multiple sclerosis (MS) is still contradictory, we analyzed naive PD1- and PD1+ T_reg cells in peripheral blood and cerebrospinal fluid (CSF) of relapsing-remitting multiple sclerosis (RR-MS) patients and of healthy control subjects. Results showed that 1) CSF PD1- T_reg cells were significantly augmented in MS patients; 2) PD1- T_reg cells were significantly increased in the peripheral blood of patients with stable disease (SMS) compared to those with acute (AMS) disease, and in patients responding to glatiramer acetate (COPA) compared to AMS- and COPA-unresponsive patients; and 3) PD1+ T_reg cells were similar in CSF and peripheral blood of all groups analyzed. PD1- T_reg cells were not increased in the peripheral blood of interferon- (IFN) -responsive patients, but the suppressive ability of T_reg cells was significantly higher in SMS and in COPA- or IFN-responsive compared to AMS- and COPA-unresponsive individuals. The data herein suggest that PD1- T_reg cells play a pivotal role in MS and offer a biological explanation for disease relapse and for the mechanism associated with response to COPA and IFN.—Saresella, M., Marventano, I., Longhi, R., Lissoni, F., Trabattoni, D., Mendozzi, L., Caputo, D., Clerici, M. CD4+CD25+FoxP3+PD1- regulatory T cells in acute and stable relapsing-remitting multiple sclerosis and their modulation by therapy.