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

Abstract

Granulomas, the hallmark of tuberculosis (TB) disease, can both restrict <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) 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 <i>Mtb</i>-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 <i>Mtb</i> 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.