Submitted July 6, 2007
Accepted January 6, 2008
Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways
Jerome D Coudert, Leonardo Scarpellino, Frederic Gros, Eric Vivier, and Werner Held*
Ludwig Institute for Cancer Research, Lausanne Branch and University of Lausanne, Epalinges, Switzerland
Centre d'Immunologie de Marseille-Luminy, Universite de la Meditarranee, Campus de Luminy, Marseille, France
* Corresponding author; email: wheld{at}isrec.unil.ch.
NKG2D is a multi-subunit activation receptor, which allows NK cells to detect and eliminate stressed, infected and transformed host cells. However, the chronic exposure of NK cells to cell-bound NKG2D ligands has been shown to impair NKG2D function both in vitro and in vivo. Here we have tested whether continuous NKG2D engagement selectively impacted NKG2D function or whether heterologous NK cell activation pathways were also affected. We find that sustained NKG2D engagement induces cross-tolerization of several unrelated NK cell activation receptors. We show that receptors that activate NK cells via the DAP12/KARAP and DAP10 signaling adaptors, such as murine NKG2D and Ly49D, cross-tolerize preferentially NK cell activation pathways that function independent of DAP10/12, such as antibody-dependent cell mediated cytotoxicity and missing self-recognition. Conversely, DAP10/12-independent pathways are unable to cross-tolerize unrelated NK cell activation receptors such as NKG2D or Ly49D. These data define a class of NK cell activation receptors that can tolerize mature NK cells. The reversible suppression of the NK cells' cytolytic function likely reduces the NK cells' efficacy to control endogenous and exogenous stress yet may be needed to limit tissue damage.
