Macrophage-T cell interactions promote SLAMF1 expression for enhanced TB defense

CD4+ T cells are essential for controlling Mycobacterium tuberculosis (Mtb) infection, yet the specific mechanisms by which they enhance macrophage-mediated bacterial control remain poorly understood. This study investigates how cognate interactions between Mtb-infected macrophages and antigen-specific CD4+ T cells modulate macrophage gene expression and antimicrobial function.

The researchers used RNA sequencing to profile gene expression in macrophages co-cultured with antigen-specific CD4+ T cells. They identified Signaling Lymphocyte Activating Molecule family member 1 (SLAMF1/CD150) as a highly induced cell surface receptor. Using flow cytometry, transwell assays, and conditional knockout mice (Slamf1fl/fl LysM-Cre+), the team evaluated the necessity of direct cell-cell contact for SLAMF1 induction and its subsequent role in controlling Mtb burden in vivo and in vitro.

SLAMF1 is uniquely upregulated on macrophages following direct, antigen-specific interaction with CD4+ T cells. This induction is dependent on adaptive immunity and autophagy. In vivo, SLAMF1 expression is significantly higher on infected macrophages compared to uninfected bystanders. Mice lacking SLAMF1 in myeloid cells exhibit increased bacterial burdens, more rapid disease progression, and altered inflammatory responses, including higher IL-1β levels. Mechanistically, SLAMF1 promotes the generation of reactive oxygen species (ROS) within the macrophage, creating a hostile intracellular environment that restricts Mtb replication.

These findings provide a molecular link between T cell-mediated adaptive immunity and innate macrophage effector functions. Because SLAMF1 expression serves as a marker for successful macrophage-T cell interaction, it may be a valuable tool for assessing immune efficacy in vaccine studies and clinical settings. Furthermore, the identification of SLAMF1 as a critical mediator of Mtb control suggests that targeting this pathway could offer a strategy for host-directed therapies to improve TB defense.