Research Briefing

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  • Cancer cells often overexpress CD47, which triggers the macrophage receptor SIRPα to elude anti-tumor immunity. We found that CD47 also suppresses phagocytosis by masking a pro-phagocytic ligand, SLAMF7, on tumor cells. We generated a first-in-class SLAMF7 antibody, which dissociated the CD47–SLAMF7 cis interaction, enabling anti-tumor immunity during SIRPα blockade.

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  • Genetic and environmental diversity are major drivers of macrophage transcriptional responses, but the mechanisms that underlie the relative contributions of gene-by-environment interactions to transcriptional responses of tissue macrophages are unclear. We defined the relative effect of cis regulation, cell-autonomous trans regulation, and non-cell-autonomous trans regulation of Kupffer cell gene expression.

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  • Kupffer cells, hepatic resident macrophages, are the first line of defense against liver metastases by engulfing disseminated malignant cells. We found that ERMAP expressed on tumor cells binds to galectin-9 and dectin-2 on Kupffer cells to deliver pro-phagocytosis ‘eat me’ signals to Kupffer cells to restrict liver metastases.

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  • That regulatory T cells can change their phenotypes has been shown in mouse models of atherosclerosis and other autoimmune diseases. We suspected that this phenomenon would also be true in humans. To test this hypothesis, we developed a strategy to identify human ‘exTreg’ cells and found that they express a cytotoxic transcriptome.

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  • We show that multivalent epitope display on the surface of viral-sized particles functions as a ‘stand-alone’ danger signal by evading inhibitory pathways to trigger a unique mode of B cell receptor signaling. The activation, survival and proliferation of B cells stimulated with particulate antigen is highly enhanced compared with those stimulated with soluble antigen, and does not require co-stimulation from T cells.

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  • Glioblastoma is a devastating primary brain tumor consisting of multiple cell populations. We identified TFPI2 as the crucial effector of the symbiotic interaction between glioblastoma stem cells and microglia. Blockade of this symbiosis inhibited tumor growth and synergized with an immune checkpoint inhibitor in mouse models of glioblastoma.

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  • Human mucosal-associated invariant T (MAIT) cells exhibit many functions, but whether this reflects different subsets is unknown. We defined the transcriptional and clonal landscape of MAIT cells in human blood and liver. Our study reveals limited transcriptional variation within tissues, but marked phenotypic and functional plasticity according to tissue, clone, and most notably, stimulus.

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  • In a genome-wide protein quantitative trait locus study, we identify the genetic determinants of the levels of 91 inflammation-related proteins in blood from over 15,000 people. By combining these data with studies on the genetics of immune-mediated diseases, we reveal how individual proteins contribute to specific disease risks.

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  • We have used human-derived stem cells to generate various microglial states and investigate the function of human microglia in a scalable manner. We were able to model disease-associated microglia that replicated transcriptional signatures found in human tissue, and further developed a lentiviral transfer system to manipulate human microglial states in vitro.

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  • Cytotoxic T cells fight pathogens and cancer by forming stereotyped cytotoxic immune synapses with infected or transformed target cells. We found that architectural changes in apoptotic target cells trigger the dissolution of immune synapses, providing a mechanistic basis for efficient synaptic turnover and serial killing.

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  • Susceptibility to respiratory pathogens is increased during early life, yet children can mount highly effective immune responses to novel pathogens in the absence of a fully developed immune system. We found that bronchus-associated lymphoid tissue (BALT) develops in the lungs early in life and supports germinal center formation and B cell differentiation to produce antibodies specific for respiratory pathogens, revealing a mechanism for immune protection in an as-yet-undeveloped immune system.

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  • The mechanisms by which TH17 cells can either protect barrier tissues or initiate autoimmunity remain unknown. Here we identify the transcription factor EGR2 as a key determinant of TH17 cell pathogenicity. EGR2 was found to govern TH17 cell migration, regulate the expression of pathogenicity-associated genes, and facilitate the recruitment of other immune cells in the central nervous system.

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  • Tumor cells exploit G-protein-coupled receptor (GPCR) signaling networks to promote angiogenesis, grow and metastasize. We show that tumor cells leverage a GPCR–Gαs–protein kinase A (PKA) signaling axis to polarize CD8+ T cells into a dysfunctional state, thereby limiting the tumor infiltration and cytotoxic function of these cells and reducing the efficacy of current immunotherapies.

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  • We identified an abundant macrophage population with a distinct transcriptomic signature in the murine mammary gland and milk during lactation. These macrophages are monocyte-derived, depend on colony-stimulating factor (CSF-1) and reside adjacent to alveoli. Human milk also contains macrophages comprising three subsets with a partial resemblance to the murine counterparts.

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  • Extravasation of blood into the brain and activation of innate immune cells are hallmarks and therapeutic targets in neurological diseases. We show that specific blood proteins induce distinct receptor-mediated gene programs in microglia and that the blood coagulation protein fibrin has a causal role in pathogenic innate immunity in models of neurological diseases.

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  • First Nations peoples of Australia have disproportionate rates of chronic comorbidities such as diabetes and renal disease. A study of COVID vaccination in First Nations peoples reveals that perturbed antibody responses can occur in individuals with comorbidities in a way strongly associated with altered IgG glycosylation patterns.

    Research Briefing