The intracellular enzyme indoleamine 2,3-dioxygenase (IDO), which degrades the rare and essential amino acid tryptophan and converts it into a series of biologically active catabolites, has been linked to the regulation of immune tolerance by specific dendritic cell subsets, and to the downmodulation of exacerbated immune responses. Although the immunoregulatory effects of IDO may be in part due to generalized suppression of cell proliferation caused by tryptophan starvation, there is also evidence that tryptophan catabolites could be directly responsible for some of the observed effects. In this report, we investigated the consequences of IDO activity, particularly with regard to the effects of tryptophan-derived catabolites, on the cytokine responses of activated invariant natural killer T (iNKT) cells, a specialized T cell subset known to have immunoregulatory properties. Our results showed that pharmacologic inhibition of IDO skewed cytokine responses of iNKT cells towards a Th1 profile. In contrast, the presence at low micromolar concentrations of the tryptophan catabolites l-kynurenine, 3-hydroxy-kynurenine, or 3-hydroxy-anthranilic acid shifted the cytokine balance towards a Th2 pattern. These findings have implications for our current understanding of immunoregulation, and the mechanisms by which iNKT cells participate in the modulation of immune responses.
|Number of pages||10|
|State||Published - 15 Apr 2008|
Bibliographical noteFunding Information:
We thank Ms. Helen Hu for technical assistance. This work was supported by grants from the National Institutes of Health (AI45889, AI064424, AI51392, and DK20541). G.S.B. is a former Lister Institute-Jenner Research Fellow and acknowledges support from the Medical Research Council (UK), the Wellcome Trust, the Royal Society Wolfson Research Merit Award, and from the James Bardrick Research Chair. Flow cytometry studies were supported by the FACS Core Facilities of the AECOM Center for AIDS Research (NIH/NIAID AI51519) and the AECOM Cancer Center (NIH/NCI P30 CA13330).
- Indoleamine 2,3-dioxygenase
- T cells
- Th1/Th2 cells
- iNKT cells