The role of NFAT in CD8+Foxp3+Tregs

Abstract CD8 +Foxp3 +regulatory T cells (CD8 Treg) correspond to a very low frequency population which can be observed during GVHD at early stage or in some cancer types. However, in vitro, around 30–60% of CD8 can express Foxp3 after induction culture with TCR stimulation and TGF-β (iCD8Treg). Why in healthy mice and humans this cell population has very low or non-frequency been still an unresolved question. In vitro, iCD8Tregs can suppress effector cells in a similar way as iCD4Treg. However, in vivo, in the IBD model, we observed that in contrast to iCD4Treg, iCD8Treg lose the Foxp3 expression and consequently their suppressive function. Also, iCD8Treg increase the IFN-γ production. These results suggest that iCD8Treg are not able to maintain the Foxp3 expression in comparison with iCD4Treg cells. What signaling pathway is responsible for the Foxp3 losing in iCD8Treg? We found a positive correlation between Foxp3 maintenance and cyclosporin A (CSA) concentration, and a reduction of IFN-γ in culture in iCD8Treg, but not for iCD4Treg. We evaluated the effect of CSA, an NFAT inhibitor, on the Tregs induction culture (with TGF-β) in the CD8 cells and found that there was no increase of Foxp3 expression. These results suggest that NFAT signaling plays a role in the Foxp3 maintenance but not in the induction of the iCD8Treg and this role is different from iCD4 Tregs.