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

Abstract

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.

Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

“…It has been recently reported that cDC1 express IDO1, and TLR ligation further increases IDO1 expression in cDC1s, whereas induces only modest expression in cDC2s ( Sittig et al., 2021 ). To exploit the pattern of IDO1 expression in human cDCs, cDC1 and cDC2 were isolated from human PBMCs from healthy donors, and IDO1 expression was measured after LPS treatment.…”

Dual Effect of Immune Cells within Tumour Microenvironment: Pro- and Anti-Tumour Effects and Their Triggers

“…On the other hand, unlike cDC1s, cDC2s are not as potent at cross-presentation; however, are the most abundant population in lymphoid and non-lymphoid tissues [ 299 ] and are better activators of human CD4 + T cells than cDC1s [ 292 ], thereby increasing the priming CD4 + T cells [ 299 , 300 ]. Recently, it has been reported that human cDC2 (also cDC1) can negatively induce the functional effects on T cell priming by IDO expression [ 301 ].…”

Targeting DCs for Tolerance Induction: Don’t Lose Sight of the Neutrophils

“…Another tolerogenic DC feature is the expression of the inhibitory receptor immunoglobulin-like transcript (ILT)-3, which has been associated with the increased generation of Tregs ( 46 , 49 , 51 , 52 ). Furthermore, immunoregulatory enzymes can be upregulated by tolerogenic DCs, such as indoleamine-2,3-dioxygenase (IDO), which leads to a decreased T-cell proliferation and the induction of Tregs ( 53 – 55 ). Taken together, compared to immunogenic DCs, tolerogenic DCs are generally characterized by lower expressions of CD80/86, MHCII, and IL-12, while they secrete TGF-β and IL-10 and express tolerogenic markers such as PD-L1, ICOSL, ILT-3, and IDO.…”