Human type 1 and type 2 conventional dendritic cells express indoleamine 2,3‐dioxygenase 1 with functional effects on T cell priming

• Published in: European journal of immunology Vol. 51; no. 6; pp. 1494 - 1504
• Main Authors: Sittig, Simone P., van Beek, Jasper J. P., Flórez‐Grau, Georgina, Weiden, Jorieke, Buschow, Sonja I., van der Net, Mirjam C., van Slooten, Rianne, Verbeek, Marcel M., Geurtz, P. Ben H., Textor, Johannes, Figdor, Carl G., de Vries, I. Jolanda M., Schreibelt, Gerty
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.06.2021; John Wiley and Sons Inc
• Subjects: Amino acids; Basic; Cancer vaccines; cDC1; cDC2; Cell growth; Cell proliferation; Clinical trials; Dendritic cells; Dioxygenase; Enzymes; epacadostat; IDO; Immune system; Immunomodulation and immune therapies; Interferon; Lymphocytes; Lymphocytes T; Peripheral blood; plasmacytoid dendritic cells; Tryptophan; cDC1; epacadostat; plasmacytoid dendritic cells; IDO; cDC2
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202048580

Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3‐dioxygenase 1 (IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrate that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN‐γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR‐stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC‐T cell cell‐cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross‐present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC‐based cancer vaccines with IDO inhibition. Among human blood dendritic cell subsets, cDC1s uniquely express biologically active IDO at steady‐state, whereas cDC2s express IDO upon IFN‐γ‐ or TLR agonist‐mediated signaling. The enzyme converts tryptophan into kynurenine, thereby limiting T cell proliferation. Selective inhibition of IDO by epacadostat impedes IDO‐mediated immunosuppressive effects in conventional DCs.