Novel CD8+ Treg suppress EAE by TGF-β- and IFN-γ-dependent mechanisms

Although CD8(+) Treg-mediated suppression has been described, CD8(+) Treg remain poorly characterized. Here we identify a novel subset of CD8+ Treg that express latency-associated peptide (LAP) on their cell surface (CD8(+)LAP(+) cells) and exhibit regulatory activity in vitro and in vivo. only a small fraction of CD8(+)LAP(+) cells express Foxp3 or CD25, although the expression levels of Foxp3 for these cells are higher than their LAP(-) counterparts. In addition to TGF-beta, CD8(+)LAP(+) cells produce IFN-gamma, and these cells suppress EAE that is dependent on both TGF-beta and IFN-gamma. In an adoptive co-transfer model, CD8(+)LAP(+) cells suppress myelin oligodendrocyte glycoprotein (MOG)-specific immune responses by inducing or expanding Foxp3(+) cells and by inhibiting proliferation and IFN-gamma production in vivo. Furthermore, in vivo neutralization of IFN-gamma and studies with IFN-gamma-deficient mice demonstrate an important role for IFN-gamma production in the function of CD8(+)LAP(+) cells. Our findings identify the underlying mechanisms that account for the immunoregulatory activity of CD8(+) T cells and suggest that induction or amplification of CD8(+)LAP(+) cells may be a therapeutic strategy to help control autoimmume processes.