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

作者：Michael Giacomantonio, Vishnu Vijay Vijayan, Preethi G. Nair, Gopal P. Pathak, Barry E. Kennedy, Joao A. Paulo, Teresa S. McMillen, Anurag Banerjee, Vishnupriyan Kumar, Mukhayyo Sultonova, Tayah B. Sommer, Nisha Owens, Unnikrishnan Babukuttan Sheela, Jawairia Atif, Sonya A. MacParland, Steven P. Gygi, J. Patrick Murphy, Shashi Gujar · 发表于：Cell Reports · 年份：2026 · DOI：10.1016/j.celrep.2026.117149 · 被引用次数：6 · 研究领域：Tryptophan and brain disorders、Psoriasis: Treatment and Pathogenesis、Stress Responses and Cortisol

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.