Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8+ T cell-macrophage interactions

• 成果类型: Article
• 署名作者: McCaffrey, Erin F.; Delmastro, Alea C.; Singh, Bindu; Devi, Annu; Munson, Caden W.; Priyanka; Golden, Nadia A.; Khader, Shabaana A.; Angelo, Michael; Kaushal, Deepak; Mehra, Smriti
• 署名单位: Stanford University; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Tulane University; University of Chicago
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2528104123
• 发表日期: 2026-08-18
• 页码: e2528104123
• 关键词: multiplexed imaging; Mycobacterium tuberculosis; granuloma; macaque; microenvironment; inflammation; infection; memory; mice; IDO

摘要

Granulomas, the hallmark of tuberculosis (TB) disease, can both restrict Mycobacterium tuberculosis (Mtb) dissemination and impede its clearance. Recent studies indicate that indoleamine 2,3-dioxygenase (IDO1), an immunosuppressive metabolic enzyme, limits infiltration of activated T cells and can contribute to TB disease progression. Treatment with 1-methyl-D-tryptophan (D-1MT), a small molecule inhibitor that restores mTOR signaling, has been shown to reduce IDO1 activity and improve immune responses in Mtb-infected rhesus macaques. Here, we investigated the impact of D-1MT treatment on TB granuloma architecture using 30-plex high-dimensional issue imaging in rhesus macaques. By spatially mapping 13 distinct cell populations, we found D-1MT treatment corresponded with significantly increased infiltration CD8+ T cells into granulomas compared to untreated controls. Notably, these CD8+ T cells expressed markers of cell proliferation and cytotoxicity. D-1MT enhanced CD8+ T cell infiltration throughout the granuloma, with particularly pronounced effects in the myeloid core, where we observed significantly enhanced spatial interactions between macrophages and CD8+ T cells, but not CD4+ T cells. Our results demonstrate that: i) effective intragranulomatous Mtb control is associated with the close spatial proximity between CD8+ T cells and macrophages, a feature less abundant in uncontrolled pulmonary TB; ii) IDO1 induction blocks CD8+ T cell infiltration and reduces T cell activation and proliferation; and iii) therapeutic strategies, including D-1MT, that improve intragranulomatous killing hold strong translational potential.