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

Sci Rep. 2017 Apr 28;7(1):1288. doi: 10.1038/s41598-017-01379-y.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4-Positive T-Lymphocytes / metabolism*
  • Female
  • Interferon-alpha / metabolism
  • Ligands
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism*
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Receptor, Interferon alpha-beta / metabolism
  • T-Lymphocytes, Regulatory / metabolism*

Substances

  • Interferon-alpha
  • KLRK1 protein, human
  • Klrk1 protein, mouse
  • Ligands
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptor, Interferon alpha-beta