Mouse models are frequently used to develop treatments for human cancer. However, the degree to which their tumor microenvironments (TMEs) are synonymously assembled is particularly poorly characterized. Through systematic immunoprofiling of 15 commonly used mouse models, we found that most murine TMEs recapitulate the composition of poorly infiltrated human tumors, extensively...
Inflammatory responses are associated with recruitment of monocyte-derived cells (Mdcs) into tissues. Although tissue-specific Mdc reprogramming is well established, how Mdc infiltration alters tissue metabolism remains unclear. Here, using a mouse neuroinflammation model coupled with genetic fate mapping, metabolomics and metabolite imaging, we identify that central nervous...
Celiac disease (CeD) is an autoimmune disorder triggered by dietary gluten. While HLA-DQ2/8-mediated presentation of gliadin peptides is required for disease, the mechanisms that underlie the loss of oral tolerance to gluten remain incompletely understood. Long-noncoding RNAs (lncRNAs) have been increasingly recognized as regulators of immune function, yet their role in oral...
Allergic asthma is driven by type 2 immune responses, including type 2 innate lymphoid cells (ILC2s). Although ILC2s are activated by the tissue alarmins interleukin (IL)-33 and IL-25, these signals do not intrinsically enforce type 2 identity and the mechanisms that maintain type 2 cytokine expression remain unclear. Here we show that allergen-induced IL-33 and IL-25 rapidly...
Germinal center B cell responses are defined by many positive regulators of affinity maturation, but few components that restrain clonal dominance, notably Nr4a1, are known. We reveal an unsuspected role for BLIMP1 (Prdm1)—a plasma cell determinant—as a feedback regulator of affinity maturation. Single-cell RNA and B cell receptor (BCR) sequencing showed that B cell-specific...
Fibrosis is a severe pathological outcome of many chronic diseases, yet the therapeutic potential of targeting the altered major histocompatibility complex (MHC) class I immunopeptidome remains largely unexplored. Here we characterized the MHC class I immunopeptidomes from both fibrotic foci of human idiopathic pulmonary fibrosis lung explants and bleomycin-treated mice...
Tissue-resident macrophages populate nearly all organs, where they adopt tissue-specific roles essential for immune defense, tissue development and homeostasis. Their dysfunction contributes to inflammation, cancer and other diseases. Whether a dedicated macrophage population operates within the extensive vascular network, one of the body’s largest and most widely distributed...
Single-cell studies have revealed substantial microglial diversity in development, homeostasis and disease. However, a framework enabling comparison and stratification of microglial states across contexts is needed. Here we generated an atlas of myeloid cell states by single-cell RNA sequencing more than one million central nervous system cells from more than 30 physiological and...
Natural killer (NK) cells and T cells need to infiltrate solid tumors to eradicate them. Here we show programmable mechanisms that can mobilize NK and T cells to solid tumors using metabolite-sensing receptors. In vivo and in vitro CRISPR activation screens using NK-92 cells identified GPR183, GPR84, GPR34 and GPR18 as top enhancers of infiltration and chemotaxis to breast and...
Macrophages are among the most abundant immune cells in solid tumors, yet how macrophage lineage and spatial organization shape antitumor immunity remains unclear. Here we uncovered a division of labor between tissue-resident CD206hi and CD206lo interstitial macrophage (IM) subsets and Ly6c2+Fn1+Vcan+ recruited macrophages (recMacs) in lung cancer. Using single-cell and spatial...
Immune interventions toward an HIV cure have focused on rejuvenating adaptive immune responses. Herein we provide a framework that features epigenetic programming of myeloid and CD4+ T cells as a major mechanism that promotes decay of the HIV reservoir. Coordinate regulation of gene expression and chromatin accessibility of pathways of innate antiviral immunity was associated...
Short-term boosting of the currently licensed rVSV∆G-ZEBOV-GP vaccine does not generate lasting antibody respones to Ebola virus (EBOV), prompting interest in strategies that elicit more durable immunity. Here, we elucidated the longitudinal humoral immune repertoire over 3 years following prime and boost rVSV∆G-ZEBOV-GP vaccinations administered 18 months apart in healthy adults...
Nonparenchymal central nervous system (CNS)-associated macrophages (CAMs) mediate immune responses at brain boundaries. Perivascular and leptomeningeal CAMs are collectively termed subdural CAMs (sdCAMs). Both sdCAMs and juxtaneuronal microglia are derived from embryonic yolk sac precursors, long-living and maintain their populations through self-renewal. Following depletion...
Neutrophil extracellular traps (NETs) constitute a vital antimicrobial defense mechanism of neutrophils, contributing to various physio-pathological processes; however, the role of plasma membrane asymmetry in this process remains unknown. Here we identify Xk-related protein 8 (XKR8), a plasma membrane phospholipid scramblase, as a pivotal regulator of NETs formation. Upon NETs...
Antiretroviral therapy (ART) interruption typically leads to rapid HIV-1 viral rebound in people with HIV-1. To develop an HIV-1 cure, insight into immunological mechanisms capable of preventing HIV-1 viral rebound is urgently needed. Here, we describe three exceptional post-intervention controllers (PICs) who maintained ART-free virological control for >6.5 years (ongoing), >7.5...
The clearance of dying cells by phagocytes (efferocytosis) is important for maintenance of tissue homeostasis and the active repression of inflammatory responses but can promote an immunosuppressive tumor microenvironment. Here we show that Notch signaling is suppressed actively during efferocytosis and that activation of this pathway by ectopic expression of the Notch...
Fibroblast–macrophage crosstalk is well-established in vitro, and fibroblast-derived colony-stimulating factor 1 (CSF1) supports macrophages in select tissues. However, whether macrophages regulate fibroblasts in vivo remains unknown. Leveraging genetic mouse models, single-cell multi-omics, flow cytometry and imaging, we show that fibroblast depletion or loss of fibroblast...
Metabolic activity shapes cell fate but remains challenging to capture in vivo with high resolution. Here we performed longitudinal metabolic and phenotypic profiling of human antigen-specific CD8+ T cells after yellow fever vaccination using flow cytometry and single-cell RNA sequencing. As assessed by protein translation rates, CD8+ T cells upregulated glycolysis to fuel...