Subversion of kynurenine-induced AHR activation in CD8 T cells by kynureninase-expressing antigen-presenting cells
Michael A Giacomantonio1, Vishnu Vijay Vijayan2, Preethi G Nair2
1Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
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 toward 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 IFN-γ production in CD8+ T cells. This highlights the importance of KYNU-expressing APCs in combating kynurenine-induced immune suppression against tumors.
Insights
Kynurenine suppresses CD8+ T cells via aryl hydrocarbon receptor (AHR) activation. However, kynureninase (KYNU)-expressing antigen-presenting cells (APCs) can degrade kynurenine, blocking immunosuppression and restoring anti-tumor immunity.
Area of Science:
- Immunology
- Metabolism
- Cancer Biology
Background:
- Kynurenine, a tryptophan metabolite, inhibits CD8+ T cell anti-tumor activity through aryl hydrocarbon receptor (AHR) activation.
- The role of kynurenine in adaptive immunity and its regulation by kynureninase (KYNU) are not fully understood.
- Indoleamine 2,3-dioxygenase 1 (IDO1) produces kynurenine, which is then degraded by KYNU, primarily outside the liver.
Purpose of the Study:
- To investigate the expression and function of kynureninase (KYNU) in antigen-presenting cells (APCs) and its impact on kynurenine-induced immunosuppression.
- To determine whether KYNU-expressing APCs can counteract the suppressive effects of kynurenine on CD8+ T cells.
- To elucidate the mechanisms by which KYNU in APCs influences adaptive immunity in the context of cancer.
Main Methods:
- Analysis of KYNU expression in human and mouse APCs (macrophages, dendritic cells) in vivo and in vitro.
- Assessment of KYNU's enzymatic activity in breaking down kynurenine.
- Evaluation of kynurenine uptake by CD8+ T cells and the impact of KYNU-expressing APCs on T cell function and IFN-γ production.
Main Results:
- KYNU is predominantly expressed and functionally active in various APCs, including macrophages and dendritic cells.
- CD8+ T cells take up kynurenine but lack active KYNU, leading to immunosuppression via AHR.
- KYNU-expressing APCs effectively deplete extracellular kynurenine, inhibit AHR activation, and restore CD8+ T cell IFN-γ production.
Conclusions:
- KYNU expression in APCs is crucial for mitigating kynurenine-induced immunosuppression.
- APCs expressing KYNU play a protective role against kynurenine-mediated suppression of anti-tumor CD8+ T cell responses.
- Targeting KYNU in APCs represents a potential strategy to enhance anti-tumor immunity.
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