Type I IFN-mediated NET release promotes Mycobacterium tuberculosis replication and is associated with granuloma caseation.

Neutrophils are the most abundant cell type in the airways of tuberculosis patients. Mycobacterium tuberculosis (Mtb) infection induces the release of neutrophil extracellular traps (NETs); however, the molecular regulation and impact of NET release on Mtb pathogenesis are unknown. We find that during Mtb infection in neutrophils, PAD4 citrullinates histones to decondense chromatin that gets released as NETs in a manner that can maintain neutrophil viability and promote Mtb replication.

Type I IFN signaling in the absence of IRGM1 promotes M. tuberculosis replication in immune cells by suppressing T cell responses.

Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells.

BHLHE40 Regulates Myeloid Cell Polarization through IL-10-Dependent and -Independent Mechanisms.

Better understanding of the host responses to Mycobacterium tuberculosis infections is required to prevent tuberculosis and develop new therapeutic interventions. The host transcription factor BHLHE40 is essential for controlling M. tuberculosis infection, in part by repressing Il10 expression, where excess IL-10 contributes to the early susceptibility of Bhlhe40-/- mice to M.

Autophagy promotes efficient T cell responses to restrict high-dose Mycobacterium tuberculosis infection in mice.

Although autophagy sequesters Mycobacterium tuberculosis (Mtb) in in vitro cultured macrophages, loss of autophagy in macrophages in vivo does not result in susceptibility to a standard low-dose Mtb infection until late during infection, leaving open questions regarding the protective role of autophagy during Mtb infection. Here we report that loss of autophagy in lung macrophages and dendritic cells results in acute susceptibility of mice to high-dose Mtb infection, a model mimicking active tuberculosis. Rather than observing a role for autophagy in controlling Mtb replication in macrophages, we find that autophagy suppresses macrophage responses to Mtb that otherwise result in accumulation of myeloid-derived suppressor cells and subsequent defects in T cell responses.

Type I IFN signaling in the absence of IRGM1 promotes replication in immune cells by suppressing T cell responses.

Polymorphisms in the gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of , , is also essential for controlling (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells.

Autophagy prevents early proinflammatory responses and neutrophil recruitment during Mycobacterium tuberculosis infection without affecting pathogen burden in macrophages.

The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models during M. tuberculosis infection and, therefore, must be tightly regulated.

Select autophagy genes maintain quiescence of tissue-resident macrophages and increase susceptibility to Listeria monocytogenes.

Innate and adaptive immune responses that prime myeloid cells, such as macrophages, protect against pathogens. However, if left uncontrolled, these responses may lead to detrimental inflammation. Macrophages, particularly those resident in tissues, must therefore remain quiescent between infections despite chronic stimulation by commensal microorganisms.

Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival.

CLEC16A is in a locus genetically linked to autoimmune diseases including multiple sclerosis, but the function of this gene in the nervous system is unknown. Here we show that two mouse strains carrying independent Clec16a mutations developed neurodegenerative disease characterized by motor impairments and loss of Purkinje cells. Neurons from Clec16a-mutant mice exhibited increased expression of the autophagy substrate p62, accumulation of abnormal intra-axonal membranous structures bearing the autophagy protein LC3, and abnormal Golgi morphology.

Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis.

Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, which is characterized in part by pulmonary abnormalities, including recurrent infections. We found that Epg5-deficient mice exhibited elevated baseline innate immune cellular and cytokine-based lung inflammation and were resistant to lethal influenza virus infection. Lung transcriptomics, bone marrow transplantation experiments, and analysis of cellular cytokine expression indicated that Epg5 plays a role in lung physiology through its function in macrophages.

T cell-mediated delay of spontaneous mammary tumor onset: increased efficacy with in vivo versus in vitro activation.

Peripheral tolerance to shared Ags expressed on both tumors and normal self-tissues presents a major barrier to T cell-based immunotherapy as a treatment for cancer. To assess the activity of tumor-specific T cells against spontaneously arising carcinomas in the context of shared Ag expression, we developed a model system whereby an identified tumor Ag, tumor ERK (tERK), is expressed transgenically on both normal mammary tissue and spontaneous mammary carcinomas. Transfer of in vitro-activated, tERK-specific DUC18 T cells delayed spontaneous tumor development in tERK-expressing mice when T cells were given before the development of palpable carcinomas.