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The glycolipid α-galactosylceramide (α-GalCer), when presented on CD1 molecules by antigen presenting cells (APCs) to invariant NKT (iNKT cells), is a potent immunomodulator. Indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing the catabolism of l-tryptophan along the kynurenine pathway, is inducible in APC and represents one of the main endogenous mechanisms of T cell homeostasis, peripheral tolerance and immunosuppression. No data have been published yet on the effect of α-GalCer on IDO in APC. We aimed to determine if: (1) α-GalCer modulates IDO in APC; (2) the α-GalCer-induced effect on IDO correlates with the production by APC of active compounds; (3) the medium from α-GalCer-treated APC is able to stimulate iNKT cells. From our results α-GalCer alone did not modify IDO expression (RT-PCR) in APC, but when human peripheral blood mononuclear cells (PBMC), monocytes, and monocytic cell lines (THP-1), expressing high levels of CD1d, were treated with interferon-γ (IFN-γ) plus α-GalCer a significant potentiation of IDO transcription was measured. This effect was not induced by increased IFN-γ release by APC, and it was functionally correlated with increased l-kynurenine (l-KYN) release by α-GalCer-treated CD1d-transfected THP-1 cells. The medium of these cells stimulated iNKT hybridoma cells to release interleukin (IL)-2, while α-GalCer alone resulted ineffective. The data demonstrate that α-GalCer: (1) does not induce IFN-γ release by APC; (2) potentiates IFN-γ-induced IDO expression and function in APC; (2) requires CD1d molecules for inducing these effects; (3) induces the release by APC of compounds active in stimulating iNKT cells.