Submitted March 2, 2006
Accepted July 25, 2006
The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46 and NKG2D activating receptors and regulates NK cell function
Mariella Della Chiesa, Simona Carlomagno, Guido Frumento, Mirna Balsamo, Claudia Cantoni, Romana Conte, Lorenzo Moretta, Alessandro Moretta*, and Massimo Vitale
DI.ME.S. Dipartimento di Medicina Sperimentale Universita di Genova, Genova, Italy
IST - Istituto Nazionale per la Ricerca sul Cancro - Genova, Italy
Istituto G. Gaslini - Genova-Quarto, Italy
Istituto G. Gaslini - Genova, Italy
IST - Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
* Corresponding author; email: alemoret{at}unige.it.
ABSTRACT
Tryptophan (Trp) catabolism mediated by indoleamine 2,3-dioxygenase (IDO) plays a central role in the regulation of T cell-mediated immune responses. In this study we demonstrate that also NK cell function can be influenced by IDO. Indeed, L-kynurenine, a Trp-derived catabolite resulting from IDO activity, was found to prevent the cytokine-mediated up-regulation of the expression and function of specific triggering receptors responsible for the induction of NK cell-mediated killing. The effect of L-kynurenine appears to be restricted to NKp46 and NKG2D, while it does not affect other surface receptors such as NKp30 or CD16. As a consequence, L-kynurenine-treated NK cells display impaired ability to kill target cells recognized via NKp46 and NKG2D. Instead, they maintain the ability to kill targets, such as Dendritic Cells (DC), that are mainly recognized via the NKp30 receptor. The effect of L-kynurenine, which is effective both at the transcriptional and at the protein level, can be reverted, since NK cells were found to recover their functional competence after washing.
