IFN-?– and IL-10–expressing virus epitope-specific Foxp3(+) T reg cells in the central nervous system during encephalomyelitis

Zhao, Jingxian; Zhao, Jincun; Fett, Craig; Trandem, Kathryn; Fleming, Erica; Perlman, Stanley

time that virus-specific effector CD4 T cells could be identified (Haring et al., 2001) , and were present at approximately the same frequency in both the acute and chronic stages of the infection (Fig. 2 , C and D). In addition, after stimulation with anti-CD3 mAb, the fraction of T reg cells expressing IFN- increased two-to fourfold, suggesting that M133 + S358-specific T reg cells accounted for only a fraction of all IFN- + T reg cells in the CNS (Fig. 2, B-D) . Notably, the mean fluorescence intensity of IFN- expression was lower in M133 + S358-specific T reg cells compared with effector CD4 T cells, indicating less expression on a per-cell basis (Fig. 2 F) . To verify that T reg cells produce IFN- in vivo, we treated B6 mice with brefeldin A (BFA) at 6 d after infection (Fig. 2 E; Liu and Whitton, 2005) . In the absence of BFA, some Foxp3  CD4 T cells were IFN- + , consistent with results showing that cells in the infected brain express IFN- in the absence of ex vivo stimulation (Fig. 2 A) . The frequency of Foxp3  and Foxp3 + cells expressing IFN- increased twofold and In this paper, we identify two epitopes (M133 and S358) targeted by T reg cells in the rJ2.2-infected central nervous system (CNS). Both epitopes are also recognized by effector T cells (Haring et al., 2001) . These virus epitope-specific T reg cells express both IL-10 and IFN-, suppress proliferation of virus-specific effector cells after stimulation with cognate peptide, and are present throughout the acute and resolution phases of the infection. Virus-specific T reg cells appear to arise, at least in part, from natural T reg cell pools because they are detected in naive Foxp3 gfp mice and mice retrogenic (Rg) for an M133-specific T cell receptor (TCR) and express the transcription factor helios.