Kynurenine-AhR reduces T-cell infiltration and induces a delayed T-cell immune response by suppressing the STAT1-CXCL9/CXCL10 axis in tuberculosis  

作　　者：Xin Liu Mengjie Yang Ping Xu Mingwei Du Shanshan Li Jin Shi Qiang Li Jinfeng Yuan Yu Pang 

机构地区：[1]Department of Bacteriology and Immunology,Beijing Chest Hospital,Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing,China [2]The Affiliated Infectious Diseases Hospital,Suzhou Medical College,Soochow University,Suzhou,China [3]Department of Tuberculosis,Beijing Chest Hospital,Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing,China

出　　处：《Cellular & Molecular Immunology》2024年第12期1426-1440,共15页中国免疫学杂志(英文版)

基　　金：supported by the National Key Research and Development Program of China(2022YFC2302901);the National Natural Science Foundation of China(82272346,82072243,82202530);the Sponsored by Beijing Nova Program(20220484169,20230484295);the Provincial Key Research and Development Program of Jiangsu in Social Development(BE2023718).

摘　　要：Tuberculosis,caused by Mycobacterium tuberculosis(Mtb),is a critical global health issue that is complicated by the ability of the pathogen to delay the host’s T-cell immune response.This delay in T-cell recruitment to the site of infection is a pivotal survival strategy for Mtb,allowing it to establish a persistent chronic infection.To investigate the underlying mechanisms,this study focused on Mtb’s exploitation of host tryptophan metabolism.Mtb upregulates indoleamine 2,3-dioxygenase 1(IDO1)in inflammatory macrophages,thereby increasing kynurenine(Kyn)production.Kyn then activates the aryl hydrocarbon receptor(AhR),leading to the upregulation of suppressor of cytokine signaling 3 and subsequent inhibition of the JAK-STAT1 signaling pathway.This results in reduced secretion of the chemokines CXCL9 and CXCL10,which are crucial for T-cell recruitment to the lungs.Supported by in vivo mouse models,our findings reveal that disrupting this pathway through AhR knockout significantly enhances T-cell infiltration and activity,thereby undermining Mtb-induced immunosuppression.In contrast,additional Kyn injection obviously inhibited T-cell infiltration and activity.These results highlight potential therapeutic targets of AhR and IDO1,offering new avenues for enhancing the host immune response against tuberculosis and guiding future vaccine development efforts.

关 键 词：Mycobacterium tuberculosis Tryptophan metabolism IDO1 IMMUNOSUPPRESSION CHEMOKINES 

分 类 号：R392[医药卫生—免疫学]