CUT&Tag assay of AHR in tuberculosis

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a critical global health issue, complicated by the pathogen’s ability 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 focuses 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 an upregulation of suppressor of cytokine signaling 3 and subsequent inhibition of the JAK-STAT1 signaling pathway. This results in reduced secretion of CXCL9 and CXCL10 chemokines, 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. On the contrary, additional Kyn injection obviously inhibited T cell infiltration and activity. These results highlight potential therapeutic targets in AhR and IDO1, offering new avenues to enhance the host’s immune response against tuberculosis and guiding future vaccine development efforts.