The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function.
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 also demonstrate that natural killer (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 (DCs), that are mainly recognized via the NKp30 receptor. The effect of l-kynurenine, which is effective at both the transcriptional and the protein level, can be reverted, since NK cells were found to recover their functional competence after washing.
Della Chiesa
Mariella
M
DIMS (Dipartimento di Medicina Sperimentale), Università di Genova, Genova, Italy.
Carlomagno
Simona
S
Frumento
Guido
G
Balsamo
Mirna
M
Cantoni
Claudia
C
Conte
Romana
R
Moretta
Lorenzo
L
Moretta
Alessandro
A
Vitale
Massimo
M
D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D002478:Cells, Cultured; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D007737:Kynurenine / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D017452:Receptors, IgG / Q000096:biosynthesis / Q000276:immunology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D014364:Tryptophan / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C527085:KLRK1 protein, human; D008562:Membrane Glycoproteins; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D007737:Kynurenine; D014364:Tryptophan