NKG2D+ CD4+ T Cells Kill Regulatory T Cells in a NKG2D-NKG2D Ligand-Dependent Manner in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) features a decreased pool of CD4(+) CD25(+) Foxp3(+) T regulatory (Treg) cells. We had previously observed NKG2D(+) CD4(+) T cell expansion in contrast to a decreased pool of Treg cells in SLE patients, but whether NKG2D(+) CD4(+) T cells contribute to the decreased Treg cells remains unclear. In the present study, we found that the NKG2D(+) CD4(+) T cells efficiently killed NKG2D ligand (NKG2DL)(+) Treg cells in vitro, whereby the surviving Treg cells in SLE patients showed no detectable expression of NKG2DLs. It was further found that MRL/lpr lupus mice have significantly increased percentage of NKG2D(+) CD4(+) T cells and obvious decreased percentage of Treg cells, as compared with wild-type mice. Adoptively transferred NKG2DL(+) Treg cells were found to be efficiently killed in MRL/lpr lupus mice, with NKG2D neutralization remarkably attenuating this killing. Anti-NKG2D or anti-interferon-alpha receptor (IFNAR) antibodies treatment in MRL/lpr mice restored Treg cells numbers and markedly ameliorated the lupus disease. These results suggest that NKG2D(+) CD4(+) T cells are involved in the pathogenesis of SLE by killing Treg cells in a NKG2D-NKG2DL-dependent manner. Targeting the NKG2D-NKG2DL interaction might be a potential therapeutic strategy by which Treg cells can be protected from cytolysis in SLE patients.