In the brain, microglia are continuously exposed to a dynamic microenvironment throughout life, requiring them to adapt accordingly to specific developmental or disease-related demands. The advent of single-cell sequencing technologies has revealed the diversity of microglial transcriptional states. In this review, we explore the various contexts that drive transcriptional diversity in microglia and

Rich neural-immune interactions in the central nervous system (CNS) shape its function and create a unique immunological microenvironment for immunotherapy in CNS malignancies. Far from the now-debunked concept of CNS “immune privilege,” it is now understood that unique immunological niches and constant immune surveillance of the brain contribute in multifaceted ways to brain health and robustly influence

The brain’s border tissues serve as essential hubs for neuroimmune regulation and the trafficking of biomaterials to and from the brain. These complex tissues—including the meninges, perivascular spaces, choroid plexus, and circumventricular organs—balance the brain’s need for immune privilege with immune surveillance and blood-brain communication. Macrophages are integral components of these tissues

Alzheimer’s disease (AD) and age-related macular degeneration (AMD) represent the leading causes of dementia and vision impairment in the elderly, respectively. The retina is an extension of the brain, yet these two central nervous system (CNS) compartments are often studied separately. Despite affecting cognition vs. vision, AD and AMD share neuroinflammatory pathways. By comparing these diseases

Sensing and recognition are key properties of both the immune and nervous systems. In the immune system, pattern recognition or antigen-specific receptors represent classic motifs in innate and adaptive immunity, respectively. In the nervous system, there is a major anatomic division between how we sense stimuli from within the body (vagal sensory nervous system) and the outside world (somatosensory

The central nervous system (CNS) was once perceived as entirely shielded from the immune system, protected behind the blood-brain barrier and thought to lack lymphatic drainage. However, recent evidence has challenged many dogmas in neuroimmunology. Indeed, by means of glymphatics, brain-derived “waste” from deep within the CNS mobilizes toward immunologically active brain borders, where meningeal

The immune and sensory nervous systems detect diverse threats, from tissue damage to infection, and coordinate protective responses to restore homeostasis. Like immune cells, sensory neurons exhibit remarkable heterogeneity, with advanced genetic models revealing that distinct subsets differentially regulate immune responses. Here, we review how various immune signals engage distinct subtypes of sensory

The central nervous system (CNS) can be subdivided into distinct anatomical and functional compartments, including the parenchyma, perivascular space, leptomeninges, and dura mater, etc. Each compartment hosts distinct immune cell populations, such as monocytes and diverse macrophages, which play critical roles in local tissue homeostasis and regional disease pathogenesis. Advances in single-cell technologies

From the migration of precursor cells to the refinement of neural circuits, the immune system plays a critical role in the development of the central nervous system. As the brain resident macrophages, microglia are integral to these processes, influencing key developmental stages and contributing to circuit remodeling. Recent years have brought a wealth of new insights into how microglia regulate key

Intestinal CD4+ T cells that are specific for self-, diet-, or commensal-derived antigens are critical for host tolerance but must also be tightly regulated to prevent aberrant activation and conditions like inflammatory bowel disease (IBD). However, it is unclear how the antigen source and location dictate the intestinal TCR repertoire. Here, we hierarchically classified self-, diet-, or microbiota-dependent

(Immunity 52, 109–122.e1–e6; January 14, 2020)

Download: Download high-res image (408KB) Download: Download full-size image

cGAS-cGAMP-STING and OAS-2-5A-RNase L are evolutionarily convergent innate immune pathways. cGAMP acts as an immunotransmitter; what about 2-5A? In this issue of Immunity, Huai et al. map the transfer of 2-5A between cells, establishing it as a bona fide immunotransmitter.

Long-lived memory B cells developing from germinal centers (GCs) are important contributors to protective immunity. In this issue of Immunity, Luo et al. report that during primary responses, T cell-derived interleukin-9 potentiates differentiation of GC memory precursors into functional memory B cells in a manner dependent on the transcriptional regulator ZBTB18.

The combination of antiangiogenic and immune checkpoint inhibitor (ICI) treatment is active in solid tumors, but the mechanism of response remains unclear. In this issue of Immunity, Benmebarek et al. show that anti-vascular endothelial growth factor enhances ICI by reprogramming regulatory T cells into a fragile state.

While neuroinflammatory responses driven by microglia and astrocytes have been extensively linked to neurodegenerative disease progression in amyotrophic lateral sclerosis (ALS), the specific pathways that coordinate glial cell-dependent neuroinflammation in ALS remain poorly defined. In this issue of Immunity, Zelic et al.1 identified RIPK1 as a pivotal regulator of glial cell-driven neuroinflammation

Specialized T cells can support tissue remodeling, but how T cells contribute to mammary gland remodeling during pregnancy is not fully understood. In a recent Cell issue, Corral et al. demonstrate that self-sensing T cells migrate to the mammary gland where they optimize milk production.

The disruption of natural ecosystems caused by climate change and human activity is amplifying the risk of zoonotic spillover, presenting a growing global health threat. In the past two decades, the emergence of multiple zoonotic viruses has exposed critical gaps in our ability to predict epidemic trajectories and implement effective interventions. RNA viruses, in particular, are challenging to control

(Immunity 50, 418–431.e1–e6; February 19, 2019)

Section snippets Main textA recent study by Gasteiger and colleagues1 described a population of circulating natural killer (NK) cells that are recruited and retained in the skin for several weeks following local viral (vaccinia virus) and bacterial (Staphylococcus aureus) infections. These cells, which the authors refer to as tissue resident (tr)NK cells, exhibit increased production of effector molecules

Section snippets Main textIn their letter to Immunity, Degli-Esposti and colleagues1 discuss the potential origins of tissue-resident natural killer (trNK) cells and the inflammatory contexts enabling their differentiation. These largely unresolved issues are relevant for NK-based cellular therapies and our understanding of tissue immunity. Here, we examine key complementarities and differences between

The factors that modulate the inflammatory response in atherosclerosis are not well defined. In this issue of Immunity, Asare et al. examine the impact of a cis-regulatory element (CRE) that controls expression of HDAC9 and find that HDAC9-mediated deacetylation of NLRP3 might be the mechanism by which genetic variants in this conserved CRE influence the inflammation associated with human atherosclerosis

Neuroimmune regulation modulates responses to cardiovascular stress and injury. In this issue of Immunity, Perrotta et al. delineate a heart-brain-spleen axis that induces adaptive cardiac remodeling in response to pressure overload, highlighting a SPeak mechanism (spleen-derived PlGF efflux activates cardiac macrophages).

Receptor interaction kinase 3 (RIPK3) is a key mediator of necroptosis, initiating programmed cell death with mercenary efficiency in multiple neurodegenerative diseases. However, in this issue of Immunity, Estevez et al. demonstrate that RIPK3, like the character Deadpool, exists in duality and can also be a force for good by preventing excitotoxic neuronal death during orthoflavivirus encephalitis

CRISPR screens are widely utilized to identify genes that regulate immune function or mediate sensitivity of cancer cells to immune attack. In this issue of Immunity, Zeng et al. present a computational framework for uncovering gene targets with dual function in both cancer and immune cells and nominate TNFAIP3 as a synergistic target whose ablation strongly elicits an antitumor response.

Hepatocellular carcinoma is poorly responsive to immune checkpoint blockade. In a recent issue of Science, Varanasi et al. reveal how bile acids dampen anti-tumor CD8+ T cell responses in the liver, contributing to cancer progression and poor immunotherapy outcomes.

Lactate, the end product of both anaerobic and aerobic glycolysis in proliferating and growing cells—with the latter process known as the Warburg effect—is historically considered a mere waste product of cell and tissue metabolism. However, research over the past ten years has unveiled multifaceted functions of lactate that critically shape and impact cellular biology. Beyond serving as a fuel source