Noncanoncial inflammasome activation by cytosolic lipopolysaccharide (LPS) causes pyroptotic cell death facilitated by gasdermin D (GSDMD) pore formation. In this issue of Immunity, Huang et al. describe how cytosolic LPS in endothelial cells does not cause cell death but restrains endothelial cell proliferation.

Tuft cells are specialized taste-chemosensory cells that detect the presence of intestinal parasites and orchestrate type 2 immunity. In this issue of Immunity, McGinty et al. discover that parasitic worms, but not commensal protists, stimulate tuft cells to release cysteinyl leukotrienes to amplify anti-helminth immunity in the small intestine.

The initial molecular events and the cell type(s) responsible for the development of fibrosis are unclear. Fukushima, Satoh, et al. find that increased expression of the nuclear exosome targeting complex component Rbm7 in lung epithelial cells promotes the degradation of the long non-coding RNA NEAT1, impairs DNA repair, and triggers apoptosis. Dying epithelial cells release chemokines that recruit

In a recent issue of Cell, Yao et al. use a unique genetic strategy to study sonic hedgehog-medulloblastoma. Their results reveal a complex network in the tumor microenvironment involving the trans-differentiation of cancer cells into astrocytes to fuel tumor growth.

Self-maintaining resident macrophages populate all mammalian organs. In addition to their role as immune sentinels, macrophages also perform day-to-day functions essential to tissue homeostasis. The homeostatic functions of macrophages are regulated by so-called tissular “niches” that control the size of the macrophage population and imprint tissue-specific identity. Here, we review the mechanisms

The intestines have the essential but challenging mission of absorbing nutrients, restricting damage from food-derived toxins, promoting colonization by symbionts, and expelling pathogens. These processes are often incompatible with each other and must therefore be prioritized in view of the most crucial contemporary needs of the host. Recent work has shown that tissue-resident innate lymphoid cells

The ability of the nervous system to sense environmental stimuli and to relay these signals to immune cells via neurotransmitters and neuropeptides is indispensable for effective immunity and tissue homeostasis. Depending on the tissue microenvironment and distinct drivers of a certain immune response, the same neuronal populations and neuro-mediators can exert opposing effects, promoting or inhibiting

Group 2 innate lymphoid cells (ILC2s) regulate immunity, inflammation, and tissue homeostasis. Two distinct subsets of ILC2s have been described: steady-state natural ILC2s and inflammatory ILC2s, which are elicited following helminth infection. However, how tissue-specific cues regulate these two subsets of ILC2s and their effector functions remains elusive. Here, we report that interleukin-33 (IL-33)

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that promote immunity to pathogens at mucosal barriers, but the mechanisms regulating their development within tissues remain poorly understood. In this issue of Immunity, Oherle et al. identify a niche in the neonatal airway where stromal cell-derived insulin-like growth factor 1 (IGF1) supports the proliferation of ILC precursors and protects

Fever has beneficial effects on immune responses; however, its impact on T cell polarization is poorly understood. In this issue of Immunity, Wang et al. show that fever acts through a T cell-intrinsic SMAD4-dependent mechanism that selectively drives Th17 cell differentiation and pathogenicity in autoimmunity.

Phagocytosis of apoptotic cells via the receptor MerTK is important for immune tolerance. In this issue of Immunity, Zhou et al. report that blockade of MerTK-mediated phagocytosis mobilizes anti-tumor immunity through a mechanism that involves the transport of tumor-derived cGAMP into macrophages via the ATP-activated channel P2X7R.

Stress responses at an organism level are complex and poorly understood. In this issue of Immunity, Li et al. demonstrate that Drosophila kidney excretes blood lipids to minimize damage by reactive oxygen species and that this function is essential for animal survival.

Antibodies are key components to prevent and treat Ebola virus disease (EVD). In this issue of Immunity, Gilchuk et al. decipher the underlying mechanism of two antibodies that cooperatively target Ebolaviruses. The study provides insight into an antibody combination that potentiates antiviral activity and is able to prevent EVD in nonhuman primates.

There is no highly effective tuberculosis vaccine. Darrah et al. (2020) and Tait et al. (2019) are setting new benchmarks for protection against infection and pulmonary disease by changing the route of vaccine delivery and by using a protein subunit vaccine with a potent adjuvant.

Asthma is a common chronic respiratory disease affecting more than 300 million people worldwide. Clinical features of asthma and its immunological and molecular etiology vary significantly among patients. An understanding of the complexities of asthma has evolved to the point where precision medicine approaches, including microbiome analysis, are being increasingly recognized as an important part of

Type I interferons (IFNs) can reprogram the cholesterol biosynthetic pathway to facilitate innate immune responses. In this issue of Immunity, Xiao et al. (2020) reveal that type I IFN signaling and 7-dehydrocholesterol (7-DHC) accumulation form a positive feedback loop to amplify innate immune responses to control viral infections by activating AKT3.

Sensing tissue damage is an ancient function of immune cells that is central to the regulation of inflammation, tissue repair, and immunity. In this issue of Immunity, Lai et al. (2020) uncover a role for the C-type lectin receptor Clec2d as a sensor of cell death, which directly detects histones released during necrosis and thus contributes to inflammation and immunopathology.

Understanding how cytotoxic T cells are regulated is key for enhancing or suppressing their activity in tumor or transplantation settings. A study by Morris et al. (2020) in this issue of Immunity shows that crosslinking of inhibitory Fc receptor FcγRIIb by the suppressive cytokine Fgl2 limits cytotoxic CD8+ T cell responses by inducing T cell apoptosis.

Multiple sclerosis is a chronic inflammatory disease characterized by demyelination in the central nervous system. In this issue of Immunity, Werneberg et al. report a striking loss of synapses driven by excessive microglial pruning early in demyelinating disease, which can be rescued by inhibiting the complement component C3.

In the search for therapeutic combinations for the treatment of cancer, the pairing of targeted inhibitors of oncogenic driver pathways with immunotherapy has largely been overlooked. In Nature, Canon et al. (2019) describe how the novel KRAS-G12C inhibitor AMG 510 can potentiate immune rejection in combination with immune checkpoint blockade.

Cancer immunotherapy is a validated and critically important approach for treating patients with cancer. Given the vast research and clinical investigation efforts dedicated to advancing both endogenous and synthetic immunotherapy approaches, there is a need to focus on crucial questions and define roadblocks to the basic understanding and clinical progress. Here, we define ten key challenges facing

Therapeutics that target the T cell inhibitory checkpoint proteins CTLA-4 and PD(L)1 are efficacious across a broad range of cancers, resulting in reductions in tumor burden and increased long-term survival in subsets of patients. The significant and wide-ranging effects of these immunotherapies have prompted the clinical investigation of additional therapies that modulate anti-tumor immunity through

Cancer is a complex disease whose outcome depends largely on the cross-talk between the tumor and its microenvironment. Here, we review the evolution of the field of tumor immunology and the advances, in lockstep, of our understanding of cancer as a disease. We discuss the involvement of different immune cells at distinct stages of tumor progression and how immune contexture determinants shaping tumor

Recent years have witnessed a revolution in our understanding of microglia biology, including their major role in the etiology and pathogenesis of neurodegenerative diseases. Technological advances have enabled the identification of microglial signatures in health and disease, including the development of new models to investigate and manipulate human microglia in vivo in the context of disease. In

Promising vaccines and results from recent clinical trials of therapeutic antibodies against Ebola virus offer hope for an end to this devastating disease. We asked three investigators in the field to share their views on the remaining challenges and important future research directions as we work toward controlling Ebola virus infection.

Exhausted CD8+ T cells adopt a functionally attenuated state but still confer a certain degree of pathogen control. Chen et al. (2019), Hudson et al. (2019), and Zander et al. (2019) assign the lasting maintenance of this restrained pathogen control to an equilibrium of effector-like, transitory, terminal, and memory-like exhausted T cells.

Targeting the CTLA-4 and PD-1 "checkpoints" is an effective treatment for a number of cancers. In this issue of Immunity, Hui et al. reveal that interaction between a CTLA-4 ligand, CD80, and its counterpart in the PD-1 pathway, PD-L1, affects both PD-1 and CTLA-4 function, raising new questions about the biological effects of using checkpoint inhibitors alone and in combination.

Integrating transcriptomic, proteomic, and metabolomic data, Lercher et al. show in a mouse model of LCMV infection that type I interferon alters the expression and function of key enzymes of the urea cycle in hepatocytes. This results in altered systemic metabolism, attenuating antiviral T cell responses and ameliorating liver injury.

In this issue of Immunity, Wang et al. identify a developmental transition of neural-immune interactions from postnatal to adult lung. Their findings implicate sympathetic nerve production of dopamine as a contributor to the susceptibility of children to allergen-induced asthmatic responses.

In a recent issue of Nature, Zhang et al. (2019) describe an additional histone post-translational modification, named histone lactylation. Following increased lactate production as a consequence of M1 polarization, histone lactylation regulates the induction of an M2-like phenotype in late stages of M1 macrophage activation to promote wound healing.