Although programmed cell death can control intracellular bacterial replication, the role of cell death during systemic Salmonella infection remained elusive. In this issue of Immunity, Doerflinger et al. discover a critical but overlapping role for cell death associated caspases during Salmonella infection.

In this issue of Immunity, Kato et al. show that high-affinity vaccines targeting rare B cells capable of broadly protective antibody responses are not hindered by promotion of terminal plasmacytic differentiation. These findings provide new understanding into vaccine design and offer important insight into B cell fate decisions.

In this issue, Acharya et al. demonstrate that glucocorticoids produced by macrophages and monocytes in the tumor microenvironment induce a dysfunctional CD8+ T cell phenotype. Blocking myeloid glucocorticogenesis enhances tumor immune surveillance and responsiveness to immune checkpoint therapy.

Liver macrophages play critical roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). In this issue of Immunity, Tran et al. and Remmerie et al. reveal that Ly6Chi monocytes in NASH replace dying resident Kupffer cells, while concomitantly are differentiating into distinct lipid associated macrophages.

Personalized medicines require understanding the molecular causes of disease. In this issue of Immunity, Gruber et al. reveal that a gain-of-function JAK1 genetic variant results in a mutant protein with mosaic expression that drives multi-organ immune dysregulation via kinase dependent and independent mechanisms. The work highlights how biochemistry can inform therapies to resolve complex immune disorders

The presence of CD4+ T cells in the healthy brain parenchyma remains controversial due to the barrier function of the glia limitans. Pasciuto, Burton, Roca et al. in Cell describe the dynamic recruitment of CD4+ T cells within the brain parenchyma, their unexpected contribution to microglial maturation, and, ultimately, their influence on behavior.

Men present more frequently with severe manifestations of coronavirus disease 2019 (COVID-19) and are at higher risk for death. The underlying mechanisms for these differences between female and male individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are insufficiently understood. However, studies from other viral infections have shown that females can mount stronger

Over the past 10 years, the field of immunometabolism made great strides to unveil the crucial role of intracellular metabolism in regulating immune cell function. Emerging insights into how systemic inflammation and metabolism influence each other provide a critical additional dimension on the organismal level. Here, we discuss the concept of systemic immunometabolism and review the current understanding

Integrated immunometabolic responses link dietary intake, energy utilization, and storage to immune regulation of tissue function and is therefore essential for the maintenance and restoration of homeostasis. Adipose-resident leukocytes have non-traditional immunological functions that regulate organismal metabolism by controlling insulin action, lipolysis, and mitochondrial respiration to control

Recent studies have reported additional subpopulations of human dendritic cells (DCs), but whether they are distinct subsets has been unclear. In this issue of Immunity, Cytlak et al. and Bourdely et al. show that DC3s possess a specific precursor and represent a separate DC lineage.

In this issue of Immunity, Xu et al. reveal that dermal dendritic cells produce interleukin-31, which acts on neurons to promote wound itch. Their findings link itch associated with deeper wounds—wounds that extend beyond the epithelium—to the cells and cytokines that mediate wound healing.

Stress is linked to negative outcomes in cardiovascular diseases but exactly why is unclear. In this issue of Immunity, Xu et al. report that stress elicits glucocorticoid-induced gut permeability, in turn triggering the expansion of a population of neutrophils that can stimulate vaso-occlusive episodes.

A minor haplotype of chromosome 10q26 accounts for much of the genetic risk of age-related macular degeneration (AMD). In this issue of Immunity, Beguier et al. demonstrate that carriers of the 10q26 AMD-risk haplotype overexpress the peptidase HTRA1, which in turns results in mononuclear phagocyte persistence in an immune privileged site and pathogenic inflammation.

Chimeric antigen receptor (CAR) T cells are potent drivers of antitumor immunity, but promoting durable CAR T cell responses remains challenging. In this issue of Immunity, Li et al. (2020) show that blockade of CAR ubiquitination induces CAR recycling to the cell surface, leading to increased CAR T cell cytotoxicity and longevity by amplifying 41BB-dependent signaling and mitochondrial metabolism

Type I and III interferons (IFNs) drive effective antiviral functions but differentially affect tissue homeostasis. Using mouse models of severe inflammation, Broggi et al. and Major et al. report in Science that type III IFNs disrupt epithelial cell proliferation and differentiation in the lung.

A key goal to controlling coronavirus disease 2019 (COVID-19) is developing an effective vaccine. Development of a vaccine requires knowledge of what constitutes a protective immune response and also features that might be pathogenic. Protective and pathogenic aspects of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not well understood, partly because the virus has

Emerging evidence suggests that the effect of dietary intake on human health and disease is linked to both the immune system and the microbiota. Yet, we lack an integrated mechanistic model for how these three complex systems relate, limiting our ability to understand and treat chronic and infectious disease. Here, we review recent findings at the interface of microbiology, immunology, and nutrition

The steep rise in food allergy (FA) has evoked environmental factors involved in disease pathogenesis, including the gut microbiota, diet, and their metabolites. Early introduction of solid foods synchronizes with the “weaning reaction,” a time during which the microbiota imprints durable oral tolerance. Recent work has shown that children with FA manifest an early onset dysbiosis with the loss of

We profiled adaptive immunity in COVID-19 patients with active infection or after recovery and created a repository of currently >14 million B and T cell receptor (BCR and TCR) sequences from the blood of these patients. The B cell response showed converging IGHV3-driven BCR clusters closely associated with SARS-CoV-2 antibodies. Clonality and skewing of TCR repertoires were associated with interferon

SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding

The development, validation, and appropriate application of serological assays to detect antibodies to SARS-CoV-2 are essential to determining seroprevalence of this virus in the United States and globally and in guiding government leadership and the private sector on back-to-work policies. An interagency working group of the US Department of Health and Human Services convened a virtual workshop to

Proteolytic maturation of the pore-forming protein gasdermin D (GSDMD) by inflammasome-activated caspase-1 is crucial for initiating pyroptosis, a lytic form of cell death. In this issue of Immunity, Lui et al. report the X-ray structure of the caspase-1-GSDMD complex, mapping the interaction interfaces that determine recognition and cleavage of GSDMD by inflammatory caspases.

In this issue, Wu et al. demonstrate the importance of the neglected interferon (IFN)-independent STING signaling axis in mice. They find that although this axis is important for antiviral HSV-1 resistance, it has a pro-cancer role by promoting T cell death.

Group A Streptococcus is a common pathogen that elicits a protective humoral response against the cell wall component GlcNAc. In this issue of Immunity, New et al. demonstrate the ability of long-lived B-1 cells to be programmed by microbial colonization and early life immunization to uniquely incorporate GlcNAc reactivity in mice, establishing their critical role in mediating neonatal immune imprinting

Metabolic support for regulatory T (Treg) cells in noninflamed tumors is not well understood. In this issue of Immunity, Kumagai et. al. show how oncogene-driven fatty-acid synthesis favors Treg cells over effector T cells and how this imbalance can be overcome.

The role of keratinocyte metabolism in psoriasis is not fully elucidated. In this issue of Immunity, Lou et al. describe that interleukin-17 (IL-17) re-programs the urea cycle in keratinocytes increasing polyamines that stabilize RNA-Ag-complexes that upon cellular turnover activate dendritic cells, which amplify psoriasis inflammation.

The elevated circulating levels of cytokines associated with a variety of infectious and immune-mediated conditions are frequently termed a cytokine storm. Here, we explain the protective functions of cytokines in “ideal” responses; the multi-factorial origins that can drive these responses to become pathological; and how this ultimately leads to vascular damage, immunopathology, and worsening clinical

Faithful maintenance of immune homeostasis relies on the capacity of the cellular immune surveillance machinery to recognize “nonself”, such as the presence of pathogenic RNA. Several families of pattern-recognition receptors exist that detect immunostimulatory RNA and then induce cytokine-mediated antiviral and proinflammatory responses. Here, we review the distinct features of bona fide RNA sensors

Besides its role as the blueprint of life, DNA can also alert the cell to the presence of microbial pathogens as well as damaged or malignant cells. A major sensor of DNA that triggers the innate immune response is cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP activates stimulator of interferon genes (STING)

All lifeforms have developed highly sophisticated systems equipped to detect altered self and non-self nucleic acids (NA). In vertebrates, NA-sensing receptors safeguard the integrity of the organism by detecting pathogens, dyshomeostasis and damage, and inducing appropriate responses to eliminate pathogens and reconstitute homeostasis. Effector mechanisms include i) immune signaling, ii) restriction

Innate immune sensors that detect nucleic acids are attractive targets for therapeutic intervention because of their diverse roles in many disease processes. In detecting RNA and DNA from either self or non-self, nucleic acid sensors mediate the pathogenesis of many autoimmune and inflammatory conditions. Despite promising pre-clinical data and investigational use in the clinic, relatively few drugs