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Subversion of kynurenine-induced AHR activation in CD8 T cells by kynureninase-expressing antigen presenting cells

ABSTRACT: Kynurenine, an intermediate metabolite of tryptophan metabolism, suppresses the antitumor activity of CD8+ T cells by activating the aryl hydrocarbon receptor (AHR). Its role in adaptive immunity is poorly understood. Outside the liver, kynurenine is mainly produced by indoleamine 2,3-dioxygenase 1 (IDO1) and further degraded by kynureninase (KYNU). This report shows that KYNU is predominantly expressed in human and mouse antigen-presenting cells (APCs) in vivo, GM-CSF-differentiated macrophages and dendritic cells in vitro, and alveolar macrophages collected in situ, and is functionally active in breaking down kynurenine into catabolic products without contributing towards de novo NAD+ synthesis. Importantly, while CD8+ T cells uptake kynurenine, they lack active KYNU, leading to AHR-dependent immunosuppression. However, KYNU-expressing APCs can deplete extracellular kynurenine, prevent AHR activation, and restore IFNγ production in CD8+ T cells. This highlights the importance of KYNU-expressing APCs in combating kynurenine-induced immune suppression against tumors.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow, Macrophage

SUBMITTER: J Patrick Murphy

LAB HEAD: J Patrick Murphy

PROVIDER: PXD074605 | Pride | 2026-02-23

REPOSITORIES: Pride

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Project description:Understanding the mechanisms of host macrophage responses to M. tuberculosis (M.tb.) is essential for uncovering potential avenues of intervention to boost host resistance to infection. Macrophage transcriptome profiling revealed M.tb. infection strongly induced expression of several enzymes controlling tryptophan (Trp) catabolism. This included indole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2), which catalyze the rate-limiting step in the kynurenine pathway, producing ligands for the aryl hydrocarbon receptor (AHR). The AHR and heterodimeric partners AHR nuclear translocator (ARNT) and RELB are robustly expressed, and AHR and RELB levels further increased during infection. Infection enhanced AHR/ARNT and AHR/RELB DNA binding, and stimulated expression of AHR target genes, including that encoding the inflammatory cytokine IL1beta. AHR target gene expression was further enhanced by exogenous kynurenine, and exogenous Trp, kynurenine or synthetic agonist indirubin reduced mycobacterial viability. Comparative expression profiling revealed that AHR ablation diminished expression of numerous genes implicated in innate immune responses, including several cytokines. Notably, AHR depletion reduced expression of IL23A and IL12B transcripts, which encode subunits of interleukin 23 (IL23), a macrophage cytokine that stimulates production of IL22 by innate lymphoid cells. The AHR directly induced IL23A transcription in human and mouse macrophages through near-upstream enhancer regions. Taken together, these findings show that AHR signaling is strongly engaged in Mtb-infected macrophages, and has widespread effects on innate immune responses. Moreover, they reveal a cascade of AHR-driven innate immune signaling, as IL1B (IL-1β) and IL23 stimulate T cell subsets producing IL22, another direct target of AHR transactivation. Gene expression profiling of Mtb-infected THP-1 monocytic cells following siRNA-mediated Aryl hydrocarbon receptor (AHR) knockdown.

			Action	DRS
	315434_a07482.mzid	Mzid
	315435_a07483.mzid	Mzid
	315436_a07484.mzid	Mzid
	315437_a07473.mzid	Mzid
	315438_a07474.mzid	Mzid

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Subversion of kynurenine-induced AHR activation in CD8 T cells by kynureninase-expressing antigen presenting cells

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