Submitted June 27, 2008
Accepted December 18, 2008
Detuning CD8+ T lymphocytes by down-regulation of the activating receptor NKG2D: role of NKG2D ligands released by activated T cells
Cristina Cerboni*, Michele Ardolino, Angela Santoni, and Alessandra Zingoni
Department of Experimental Medicine, Instituto Pasteur-Fondazione Cenci Bolognetti, University of Rome "Sapienza", Rome, Italy
* Corresponding author; email: cristina.cerboni{at}uniroma1.it.
NKG2D is an activating receptor expressed on CD8+ 
+ T cells, 
+ T cells, NK cells, and on certain activated CD4+ T cells. For a long time, the interaction of NKG2D with its ligands (NKG2DLs) MICA, MICB and ULBP1-3 has been considered a mechanism for recognition and elimination of tumor, infected or otherwise "stressed" cells. However, a new role for NKG2D as an immunoregulatory receptor is now emerging. Here, we show that NKG2D is strongly down-modulated on antigen-activated CD8+ T cells but only if CD4+ T cells are present. Down-modulation was caused by soluble factors produced by CD4+ T cells, and in particular soluble NKG2DLs were found in the supernatants of antigen-activated T cell cultures. MICB was the ligand released at higher levels when CD4+ T cells were present in the cell cultures suggesting that it could be the major player of NKG2D down-modulation. CD8+ T cells expressing low levels of NKG2D had impaired effector functions, as evaluated by proliferation, cytokine production and cytotoxicity assays after combined triggering of NKG2D and TCR-CD3 complex. These findings show that activated CD4+ T cells expressing NKG2DLs can efficiently prevent NKG2D-mediated CD8+ T cell functions, and suggest that the NKG2D/NKG2DLs interaction can regulate immune responses.
