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SLAMF1 is regulated by macrophage-CD4 T cell contact and confers protection to Mycobacterium tuberculosis

ABSTRACT: CD4 T cells are crucial for protective immunity to Mycobacterium tuberculosis (Mtb). Because CD4 T cell protection depends upon direct interaction with infected macrophages, we sought to identify contact-dependent protective factors. We discovered that direct contact with antigen-specific CD4 T cells drives signaling lymphocytic activation molecule family member 1 (SLAMF1/CD150) expression on macrophages. SLAMF1 is a cell-surface receptor that mediates homotypic interactions between hematopoietic cells, interacts with microbes, and promotes macrophage antimicrobial responses. In mice, SLAMF1 expression was induced on Mtb-infected myeloid cells in a T cell-dependent manner and partially impaired in autophagy-deficient macrophages. In non-human primates, antigen presentation by lung macrophages induced SLAMF1 expression in a manner that correlated with T cell abundance and vaccine protection. Finally, in mice SLAMF1 limited Mtb burden and inflammatory responses during Mtb infection. We conclude that SLAMF1 is a T cell contact-dependent factor in macrophages that contributes to host protection from TB.

ORGANISM(S): Mus musculus

PROVIDER: GSE224054 | GEO | 2025/06/18

REPOSITORIES: GEO

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Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 1] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL?12, IL?1 and TNF??, as well as IFN?? and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL?10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease. Macrophages were derived from C57Bl/6 bone marrow, plated and infected with Mtb H37Rv (or not) in duplicate wells. Samples were then harvested for RNA at time 0 (uninfected only), 15m, 30m, 1hr, 3hr, 6hr and 24hr.

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SLAMF1 is regulated by macrophage-CD4 T cell contact and confers protection to Mycobacterium tuberculosis

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