Regulatory NK1.$ 1^{−} %$ CD4^{+} %$ NKG2D^{+} $ subset induced by $ NKG2DL^{+} $ cells promotes tumor evasion in mice

Abstract Regulatory T cells play critical roles in self-tolerance and tumor evasion. $ CD4^{+} %$ NKG2D^{+} $ cells with regulatory activity are present in patients with $ NKG2DL^{+} $ tumors and juvenile systemic lupus erythematosus. We previously showed that TGF-β-producing $ CD4^{+} %$ NKG2D^{+}...
Ausführliche Beschreibung

Abstract Regulatory T cells play critical roles in self-tolerance and tumor evasion. $ CD4^{+} %$ NKG2D^{+} $ cells with regulatory activity are present in patients with $ NKG2DL^{+} $ tumors and juvenile systemic lupus erythematosus. We previously showed that TGF-β-producing $ CD4^{+} %$ NKG2D^{+} $ T cells are present in pCD86-Rae-1ε transgenic mice. Here, we performed both ex vivo and in vivo studies on pCD86-Rae-1ε transgenic mice and an MC38 tumor-bearing mouse model and show that NK1.$ 1^{−} %$ CD4^{+} %$ NKG2D^{+} $ T cells have regulatory activity in pCD86-Rae-1ε transgenic mice. Furthermore, this T-cell subset was induced in mice transplanted with $ NKG2DL^{+} $ tumor cells and produced TGF-β and FasL, and secreted low amounts of IFN-γ. This T-cell subset downregulated the function of effector T cells and dendritic cells, which were abolished by anti-TGF-β antibody. In vivo, adoptive transfer of NK1.$ 1^{−} %$ CD4^{+} %$ NKG2D^{+} $ T cells promoted TGF-β-dependent tumor growth in mice. We further found that ex vivo induction of NK1.$ 1^{−} %$ CD4^{+} %$ NKG2D^{+} $ T cells was dependent on both anti-CD3 and NKG2DL stimulation. Furthermore, regulatory NK1.$ 1^{−} %$ CD4^{+} %$ NKG2D^{+} $ T cells did not express Foxp3 or CD25 and expressed intermediate levels of T-bet. Western-blotting showed that STAT3 signaling was activated in NK1.$ 1^{−} %$ CD4^{+} %$ NKG2D^{+} $ T cells of MC38 tumor-bearing and pCD86-Rae-1ε transgenic mice. In conclusion, we describe a regulatory NK1.$ 1^{−} %$ CD4^{+} %$ NKG2D^{+} $ T-cell population, different from other regulatory T cells and abnormally elevated in pCD86-Rae-1ε transgenic and MC38 tumor-bearing mice. Ausführliche Beschreibung