Kynurenine-AHR Reduces T-Cell Infiltration and Induces a Delayed T-Cell Immune Response by Suppressing the STAT1-CXCL9/CXCL10 Axis in Tuberculosis

Infectious Diseases Medicine Immunology Life Sciences
tuberculosis tryptophan metabolism IDO1 immunosuppression chemokines T-cell infiltration STAT1 signaling pathway

Research Background and Motivation

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a global health issue infecting and killing millions annually. Despite advances in TB diagnosis and treatment, the immune evasion strategies employed by Mtb remain a critical reason for its prolonged survival in the host, leading to chronic infections. Mtb evades immune clearance by delaying the immune response of the host’s T cells, especially through postponing the recruitment of T cells to infection sites. This delayed T-cell response is considered one of Mtb’s primary strategies to secure its ecological niche and evade the host immune system’s attack.

During TB infection, adaptive immune responses—particularly through the actions of CD4+ and CD8+ T cells—are crucial. CD4+ T cells secrete interferon-gamma (IFN-γ), which activates macrophages and enhances their bactericidal function, while CD8+ T cells can directly kill infected cells, reducing bacterial loads. However, Mtb suppresses the recruitment and functionality of T cells through various mechanisms, thereby hindering effective immune control of the infection. Studying how Mtb reprograms the host’s metabolism to interfere with immune responses, especially T-cell recruitment and function, is of great scientific significance and potential therapeutic value.

Research Context

Recent attention has focused on the role of tryptophan metabolism in immune regulation. One of the key metabolites, kynurenine (Kyn), is known as an effective immunosuppressive molecule that inhibits T-cell functions by activating the aryl hydrocarbon receptor (AHR). After Mtb infection, the host’s macrophages see a significant upregulation in tryptophan metabolism, leading to increased Kyn production. Kyn, in turn, activates AHR, further suppressing the JAK-STAT1 signaling pathway and reducing the secretion of the chemokines CXCL9 and CXCL10. This process impairs T-cell recruitment to infection sites. It is believed this mechanism is one of the primary ways Mtb evades immune attack.

However, the precise mechanism of how Kyn-AHR signaling regulates immune evasion during TB infection remains incomplete. This study seeks to elucidate how Mtb manipulates host tryptophan metabolism, particularly through the IDO1-Kyn-AHR axis, to suppress the recruitment and function of T cells, enabling immune evasion. The authors also aim to explore new therapeutic targets to improve immune responses and TB treatment.

Research Contributors and Publication Information

This study was conducted by researchers from Beijing Chest Hospital, Capital Medical University, and the Affiliated Infectious Disease Hospital, Soochow University. The primary authors include Xin Liu, Mengjie Yang, and Ping Xu, with Jinfeng Yuan and Yu Pang serving as corresponding authors. This research was published on October 22, 2024, in the Cellular & Molecular Immunology journal with the title, “Kynurenine-AHR reduces T-cell infiltration and induces a delayed T-cell immune response by suppressing the STAT1-CXCL9/CXCL10 axis in tuberculosis.”

Research Design and Process

1. Correlation Between Serum Kyn Levels and T-Cell Infiltration in TB Patients

Through liquid chromatography-mass spectrometry (LC-MS), serum Kyn levels were measured in healthy individuals and patients with active TB. Results showed significantly higher serum Kyn levels in TB patients compared to healthy individuals. When dividing TB patients into high- and low-Kyn groups, those in the high-Kyn group showed significantly reduced CD4+ and CD8+ T-cell infiltration in lung tissues. Additionally, Kyn levels correlated negatively with T-cell effector cytokines (IFN-γ, TNF-α) and positively with inhibitory receptors (e.g., PD-1, TIM3, LAG3) on T cells. These findings indicate that Mtb induces elevated Kyn production, which inhibits T-cell recruitment and functions, contributing to immune evasion.

2. Mtb Suppresses T-Cell Infiltration by Activating the IDO1-Kyn Pathway

IDO1’s (indoleamine 2,3-dioxygenase 1) role was investigated in regulating tryptophan metabolism. Following infection, Mtb significantly upregulated IDO1 expression in inflammatory macrophages while leaving other tryptophan-degrading enzymes (IDO2, TDO2) largely unaffected. IDO1 expression increased proportionally with infection dose and duration, supporting a dose-dependent mechanism. Mtb was also shown to stabilize IDO1 mRNA, increasing its expression. In vitro T-cell migration assays revealed that silencing IDO1 enhanced T-cell migration, while overexpression inhibited it. Supplementing with Kyn reversed these effects, confirming that IDO1-generated Kyn inhibits T-cell migration.

3. IDO1 Inhibits T-Cell Recruitment via the STAT1-CXCL9/10 Pathway

Further experiments revealed that IDO1 impaired T-cell migration by suppressing STAT1 signaling and reducing CXCL9 and CXCL10 chemokine production. Silencing STAT1 eliminated the migration-enhancing effects caused by IDO1 knockdown. Notably, Kyn inhibited STAT1 phosphorylation through AHR activation, disrupting CXCL9/10 expression. These findings demonstrate that the IDO1-Kyn-AHR axis suppresses T-cell recruitment to lung infection sites.

4. AHR Regulates STAT1 Signaling by Inducing SOCS3

The role of AHR in suppressing STAT1 activation was found to involve the upregulation of SOCS3 (suppressor of cytokine signaling 3). Chromatin immunoprecipitation and other assays confirmed that AHR directly binds to the SOCS3 promoter, increasing its expression. SOCS3, in turn, inhibits STAT1 activity, thereby reducing CXCL9/10 expression. Knocking down SOCS3 enhanced T-cell migration and restored chemokine levels, suggesting SOCS3 as a mediator of AHR’s immunosuppressive effects.

5. In Vivo Validation of the Kyn-AHR Pathway

In a mouse model, Kyn administration reduced lung CD4+ and CD8+ T-cell infiltration during TB infection, while CXCL9/10 levels were similarly suppressed. In contrast, AHR-deficient mice exhibited higher T-cell infiltration and chemokine expression, as well as enhanced cytokine production (IFN-γ, TNF-α). The findings suggest that the Kyn-AHR pathway not only delays T-cell recruitment but also induces their dysfunction. Additionally, AHR-silencing reduced bacterial loads in lungs and spleens, demonstrating therapeutic potential.

Conclusions and Implications

This study identifies a novel immune evasion mechanism by which Mtb exploits the host’s tryptophan metabolism via the IDO1-Kyn-AHR signaling axis to inhibit STAT1-CXCL9/10 pathways. This suppresses T-cell recruitment and functions, thereby facilitating immune evasion. By targeting AHR and related pathways, the study provides valuable insights for developing immunotherapies and vaccines.

Key Findings:

  1. Discovery of a Novel Pathway: The IDO1-Kyn-AHR axis was identified as a critical mechanism through which Mtb suppresses T-cell activity and evades immune detection.
  2. Therapeutic Potential: Blocking AHR activity may enhance T-cell responses and immune control over Mtb infection, suggesting promising therapeutic targets for TB treatment.

Study Highlights

  1. Innovative Mechanism: This work elucidates a metabolic pathway employed by Mtb to delay adaptive immune responses, providing new insight into TB immunopathology.
  2. Extensive Validation: Using advanced techniques (e.g., LC-MS, in vivo mouse models), the study rigorously validates connections between Kyn-AHR signaling, T-cell function, and immune suppression.
  3. Therapeutic Opportunities: AHR inhibition offers a strategic avenue for accelerating immune responses and improving TB control, opening new pathways for vaccine development.

Research Significance

By uncovering the role of the IDO1-Kyn-AHR axis in immune evasion, this study provides significant insight and potential solutions to major barriers in TB treatment. Future work could explore the clinical application of AHR inhibitors to boost host immunity, paving the way for innovative therapies.