Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first step in the kynurenine pathway of tryptophan (Trp) degradation that produces several biologically active Trp metabolites. L-kynurenine (Kyn), the first byproduct by IDO1, promotes immunoregulatory effects via activation of the Aryl hydrocarbon Receptor (AhR) in dendritic cells (DCs) and T lymphocytes. We here identified the nuclear coactivator 7 (NCOA7) as a molecular target of 3-hydroxyanthranilic acid (3-HAA), a Trp metabolite produced downstream of Kyn along the kynurenine pathway. In cells overexpressing NCOA7 and AhR, the presence of 3-HAA increased the association of the two molecules and enhanced Kyn-driven, AhR-dependent gene transcription. Physiologically, conventional (cDCs) but not plasmacytoid DCs or other immune cells expressed high levels of NCOA7. In cocultures of CD4+ T cells with cDCs, the co-addition of Kyn and 3-HAA significantly increased the induction of Foxp3+ regulatory T cells and the production of immunosuppressive transforming growth factor β in an NCOA7-dependent fashion. Thus, the co-presence of NCOA7 and the Trp metabolite 3-HAA can selectively enhance the activation of ubiquitary AhR in cDCs and consequent immunoregulatory effects. Because NCOA7 is often overexpressed and/or mutated in tumor microenvironments, our current data may provide evidence for a new immune check-point mechanism based on Trp metabolism and AhR.
Highlights
Immune regulation is a highly evolved form of biologic response that controls immunity and dampens exaggerated inflammation [1,2,3,4]
No effect could be detected for Biot3, incubation of mesenteric lymph node (MLN) cells with Biot1 and, more so, Biot2 determined a functional profile very similar to that induced by 3-hydroxyanthranilic acid (3-HAA) (Figures 1B–E)
Because Aryl hydrocarbon Receptor (AhR) can be activated by endogenous ligands [24], including Kyn, and because our current data indicated the occurrence of nuclear coactivator 7 (NCOA7) binding by a Trp metabolite, we investigated whether 3-HAA could favor recruitment of NCOA7 by AhR and modulate the transactivating ability of the receptor
Summary
Immune regulation is a highly evolved form of biologic response that controls immunity and dampens exaggerated inflammation [1,2,3,4]. Indoleamine 2,3-dioxygenase 1 (IDO1) and the Aryl hydrocarbon Receptor (AhR) represent two ancient metabolic molecules that may have functionally co-evolved to integrate their immunoregulatory potential [5, 6]. Dendritic cells (DCs) express the highest levels of IDO1, in response to the cytokine interferon γ (IFN-γ) [9,10,11]. Trp starvation and the production of kynurenines by DCs induce the conversion of naïve CD4+ T cells into Foxp3+ regulatory T (Treg) cells [12, 13]. The high levels of Kyn produced by DCs under inflammatory conditions—as well as by tumors—can exert immunoregulatory effects on T cells via AhR activation in the absence of Trp starvation [5, 14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
