Cholesterol unlinks innate-adaptive immune axis in tuberculosis granulomas [human]

ABSTRACT: Chronic lung infection, a long-standing global health issue, associates with compromised protective immunity against pathogens (PMID: 29062070, PMID: 27890913). Lung granulomas, consisting of immune cell aggregates, represent regional immune microenvironments formed in response to chronic infections, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB) (PMID: 36493751). However, the microenvironmental factors and mechanisms modulating protective immune response in granulomas remain incompletely understood. Here, we employ multiplex immunohistochemistry and spatial transcriptomics of human specimens and mouse models to map the locations, transcriptomes, and interactions of macrophages and T cells in TB granulomas. We identify the immune plasticity of macrophages and T cells shaped by granuloma lesion severity and their proximity to multinucleated giant cells or tertiary lymphoid structures. We further uncover a lipid-related disruption of innate-adaptive immune interplay in necrotic granulomas, with immunopathological features distinct from those of the lung tumor microenvironment. Mechanistically, this immune disruption results from Mtb-induced macrophage lysosomal cholesterol accumulation, which sequesters major histocompatibility complex II in lysosomes, thereby hindering antigen presentation and impairing T cell anti-Mtb response. Pharmacologically restoring cholesterol homeostasis of lung macrophages enhances T cell anti-Mtb protective immunity in mice. Collectively, our study reveals the lysosomal cholesterol overload-impaired innate-adaptive immune axis in granulomas, and indicates a cholesterol-targeting therapeutic strategy against chronic lung infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285046 | GEO | 2026/02/21

REPOSITORIES: GEO