Macrophages can foster pro- or anti-tumor immune environments. In this issue of Immunity, Clark et al. report that altering the composition of the mitochondrial electron transport chain reprograms macrophages toward a CXCL9hiSPP1lo immunostimulatory ph…
The induction of CD4+Foxp3+ regulatory T cells (pTreg cells) in the intestine is important for preventing allergic and inflammatory disease, but what cells drive their differentiation is less clear. Three manuscripts in Nature, Cell, and Science conclu…
Autonomic imbalance is central to heart failure (HF), but the mechanistic impact of parasympathetic withdrawal has remained unclear. Li, Zhang, Li, et al. demonstrate that targeted optogenetic stimulation of choline acetyltransferase (ChAT)-expressing …
by Artun Bülbül, Julian Hönninger, Veit R. Buchholz
Tumor-infiltrating CD8+ T cells with a tissue-resident memory phenotype have been described in both mice and humans. In this issue of Immunity, Green et al. provide a detailed analysis of the transcriptional and epigenetic regulation of these cells in …
T cells expressing the T cell receptor (TCR) Vγ9Vδ2 chains recognize butyrophilins (BTNs) in the presence of phosphorylated antigens (pAgs). In this issue of Immunity, Zhang et al. and Zhu et al. illustrate the mechanism of TCR-BTN interaction using cr…
Pancreatic ductal adenocarcinoma is an aggressive cancer characterized by an immunosuppressive tumor microenvironment and limited therapeutic options. Mahat et al. show that a prevalent p53 mutation drives the expression of the chemokine Cxcl1 by bindi…
Clark et al. reveal that tumor-derived cues induce a functional switch in tumor-associated macrophages (TAMs) through decreased expression of NDUFA4, a mitochondrial complex IV subunit. This promotes a shift from pro-tumor Spp1+ TAMs to anti-tumor Cxcl…
The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway integrates critical environmental and metabolic cues to regulate immune cell activation, differentiation, and function. Patel and Powell provide an updated comprehensive review of o…
Parasympathetic neuronal dysfunction is associated with heart failure, yet the underlying mechanism is poorly understood. Here, Li et al. demonstrate that optogenetic activation of the vagus nerve prevents the progression of heart failure by suppressin…
The microbiota’s impact on immune development is well appreciated. Mooser et al. show now that dietary LPS promotes intestinal germinal center reactions and IgA production independently of the microbiota. This work highlights how diet alone can have lo…
DOCK8-deficient patients and mice are prone to food allergy and oral anaphylaxis. Here, Janssen et al. demonstrate that DOCK8 deficiency yields expanded mucosal mast cells and elevated circulating tryptase concentrations. Loss of DOCK8 in T cells impai…
Lack of CD4+ T cell help during acute infections is known to compromise the generation of functional CD8+ T cell memory. van der Heide et al. reveal that this dysfunction is not permanent but rather a transient state of delayed memory maturation. They …
Upon reactivation, some memory B cells differentiate into protective antibody-secreting cells. Risley et al. show that the transcription factor T-bet marks a population of memory B cells poised to rapidly differentiate into antibody-secreting cells. Th…
Maintaining immune tolerance to the microbiota is essential for gut health. Zhou et al. demonstrate that ILC3s are a RORγt+ APC that sense the microbiota through STING to induce microbiota-specific Treg cells. However, if this pathway becomes uncontrol…
Human γδ T cells recognize pathogens and tumors through butyrophilin-mediated phosphoantigen sensing. However, the assembly of butyrophilin multimers and their mechanism of TCR engagement have remained unclear. Zhang et al. reveal cryo-EM structures sh…
Evolutionary medicine integrates principles of evolutionary biology to understand and treat human diseases. As a classical example, positive selection of the sickle hemoglobin mutation, which confers a survival advantage against malaria in heterozygous…
To limit hyperactive T helper (Th)1-driven pathology, it is crucial that this T cell population contracts upon pathogen clearance. In this issue of Immunity, Rahman et al. define a complement-C5-mediated lipid-class-switch mechanism that regulates Th1 …
Maternal immune activation (MIA) can cause neurodevelopmental disorders, but the underlying mechanisms are incompletely understood. In this issue of Immunity, Bian et al. show that MIA triggers decidual NK cells to secrete granzyme B, which crosses the…
Somatic mutations in hematopoietic stem cells can lead to clonal hematopoiesis of indeterminate potential (CHIP), a frequent condition associated with many age-related diseases including solid cancer. In the New England Journal of Medicine, Pich et al….
Cytotoxic antibodies have become an essential tool to remove unwanted cells in patients with cancer, infection, and autoimmunity. Wöhner and Nimmerjahn summarize recent insights into how antibody-dependent cellular cytotoxicity (ADCC) reactions proceed…
by Jared R. Coombs, Sabrina S. Burgener, Kate Schroder
Red blood cells (RBCs) undergo pathological cell death in hemolytic diseases. In a recent issue of Cell, Chen et al. reveal a mode of programmed cell death, spectosis, in which complement activation initiates (mini)NLRP3-caspase-8 complexes, culminatin…
The regulation of myeloid cell responses can determine tumor outcomes. In this issue of Immunity, Blidner et al. report that galectin-1 triggers both immunoregulatory and pro-angiogenic circuits in myeloid cells, promoting tumor growth via a VEGF-depen…
Dectin-1 is known for its role in antifungal immunity, but its contribution to pulmonary fibrosis remains poorly defined. Qiu et al. reveal that Dectin-1 signaling promotes lung fibrosis by inducing Arginase-1 and TGF-β through Raf1-dependent, CARD9-in…
Metabolic reprogramming is a hallmark of cancer. Liu et al. demonstrate that in hepatocellular carcinoma, inflammatory macrophage-driven efflux of N1-acetylspermidine operates in a charge-dependent manner to polarize CCL1+ macrophages, which in turn re…
The pathways regulating Th1 cell contraction are not well understood. Rahman et al. demonstrate that complement receptor C5aR2 controls T cell-intrinsic prostanoid metabolism as an integral component of Th1 cell contraction. Faulty C5aR2-prostanoid rew…
Polyclonal Mycobacterium tuberculosis-specific antibody-mediated effector functions correlate with improved infection in humans; however, the precise antibody specificities and functions that contribute to this control remain undefined. Grace et al. em…
Green et al. establish a multiomic single-cell atlas of antigen-specific CD8+ T cell states across infection and cancer, revealing enhancer-driven gene regulatory networks governing CD8+ T cell differentiation and tissue adaptation. They demonstrate th…
Why microglia stop reducing amyloid deposits from Alzheimer’s disease (AD) brains is unknown. Prakash, Manchanda, et al. show that microglia increase their lipid droplets and lose their phagocytic capacity with increasing Aβ exposure or proximity to pl…
Blidner et al. identify a glycosylation-dependent, galectin-driven circuit as a common mechanism that simultaneously induces immunosuppressive and pro-angiogenic functions in myeloid-derived suppressor cells, revealing therapeutic opportunities to targ…
Maternal immune activation during pregnancy is associated with neurodevelopmental disorders in offspring, yet how maternal-fetal interface perturbations influence prenatal fetal myeloid cells and induce neurodevelopmental disorders remain unclear. Bian…
ATG16L1T300A is associated with Crohn’s disease and causes immune dysfunction in mouse models, yet a plurality of humans are heterozygous carriers. Yao, Rudensky, et al. find that the ATG16L1 disease variant alters protein-protein interaction. Conseque…
The functional role of TMEM119, a homeostatic microglial marker, has not been fully elucidated under Alzheimer’s disease (AD) pathological conditions. Liu et al. demonstrate that microglial TMEM119 actively participates in the dynamic clearance of amyl…
T helper (Th) 2 cells and group 2 innate lymphoid cells (ILC2s) express similar effector molecules in response to distinct signals—TCR engagement and interleukin-33, respectively. Guichard et al. find that NF-κB is essential for type 2 cytokine product…
The critical immunoregulatory function of the lung nerve- and airway-associated macrophages (NAMs) is increasingly becoming evident. In this issue of Immunity, Yeung et al. report that NAMs’ response to type I interferon limits SARS-CoV-2 spread, infla…
Long-term consumption of diets high in fats has detrimental impacts on the immune system, but the window necessary for initiating these effects is unclear. In this issue of Immunity, Xiong et al. demonstrate that even short-term exposure to saturated f…
Liver regeneration is a remarkable and unique biological process, orchestrated by an intricate cellular crosstalk of (non-)parenchymal, immune, and nerve cells. In this issue of Immunity, Modares et al. uncover the pivotal role of choline acetyltransfe…
Pancreatic cancer has traditionally been considered refractory to immunotherapy. In a follow-up to the first clinical trial of personalized mRNA vaccines against this deadly cancer, published in Nature, Sethna et al. report compelling evidence of long-…
Sickle cell disease (SCD) inhibits CD8+ T cell function in the tumor microenvironment, potentially affecting cancer immunotherapy. Zhao, Hu, Deng, et al. reveal that SCD alters the 3D genome architecture of CD8+ T cells, triggering ferroptosis and impa…
Rapid viral evolution challenges the efficacy of vaccines and other medical interventions. Our ability to evaluate interventions is currently limited to assessments against past or circulating variants. Youssef et al. developed EVE-Vax, a computational…
HIV-1 is highly prone to mutations, and a vaccine must stimulate production of antibodies targeting conserved determinants on its exposed envelope glycoprotein (Env). Such broadly neutralizing antibodies (bNAbs) are infrequently induced by natural infe…
Initial specificity is thought to be required for somatic hypermutation (SHM)-driven antibody evolution. Zuo, Gautam, et al. demonstrate that non-cognate B cells can enter germinal centers, undergo SHM, and acquire new antigen specificities, highlighti…
Butyrophilin (BTN) receptor complexes sense phosphoantigens (pAgs) and activate Vγ9Vδ2 T cells, but the underlying mechanism remains unclear. Zhu et al. demonstrate that pAgs induce inside-out stabilization of BTN receptor complexes, promoting Vγ9Vδ2 T…
by Constanze Depp, Jordan L. Doman, Maximilian Hingerl, Judy Xia, Beth Stevens
Single-cell sequencing technologies have revealed the transcriptional diversity of microglia, the brain-resident macrophage population. In this issue, Stevens and colleagues discuss how microglia adapt to different brain contexts and how this shapes th…
The immune and sensory nervous systems work in concert to defend against threats and maintain homeostasis. In this issue of Immunity, Ugolini and colleagues review how immune signals activate specialized sensory neuron subtypes, triggering the release …
Immunotherapy for gliomas holds great promise, but overcoming current barriers to therapeutic success requires deeper understanding of the unique immunological niche of the CNS and the extensive crosstalk between brain, immune, and malignant cells. In …
Alzheimer’s disease (AD) and age-related macular degeneration (AMD) share immune-related mechanisms such as microglial activation, amyloid beta deposits, and complement dysregulation, yet also involve distinct tissue-specific responses. Butovsky and Ro…
In this review, Prinz and Frosch describe how the central nervous system is partitioned into distinct immune niches, each hosting unique myeloid cell populations that shape disease outcomes. They highlight novel cellular and molecular strategies to mod…
Specialized immune cells called border-associated macrophages (BAMs) guard the brain’s outer tissues, where they help maintain homeostasis and protect against disease. In this review, Vara-Pérez and Movahedi explore how BAMs develop, how they can be cl…
by Raffaella Morini, Erica Tagliatti, Matteo Bizzotto, Michela Matteoli
Microglia play a crucial role in regulating proper brain formation, with their activity being both spatially and temporally controlled. Matteoli and colleagues summarize the known interactions between microglia and various brain cell types during late …
Recent discoveries of glymphatics and meningeal lymphatics have redefined our understanding of CNS immunosurveillance. Kim and Kipnis illustrate how the clearance of brain-derived antigens creates an “immune code” that, when presented by meningeal anti…
Studies of peripheral neuroimmunology have unveiled sensory biology as a powerful new lens through which both immunology and neuroscience can be viewed. In this perspective, Kim and Artis discuss recent advances in sensory neuroimmunology and highlight…
The function of immune pathways in homeostatic neurobiology remains underexplored. Zengeler et al. find that the inflammasome complex, typically associated with immune responses, is involved in memory-related and seizure processes in the adult murine b…
Intestinal T cells will recognize self-, diet-, and microbiota-derived antigens to effectively promote tolerance. Here, Yi and Jung et al. present a hierarchical TCR classification to reveal complex interactions between diet and microbiota. Diet-specif…
The niche signals critical for the homeostasis and functions of the brain border-associated macrophages (BAMs) are not well understood. Van Hove et al. demonstrate that BAMs require IL-34 derived from mural cells and perivascular fibroblasts for their …
Replacing brain macrophages holds substantial therapeutic promise but remains challenging. Bastos et al. uncover the requirements for monocytes to replace microglia and border-associated macrophages. They show that monocyte ontogeny shapes brain macrop…
Hematopoietic stem cell transplant is the gold standard for treatment of globoid cell leukodystrophy, also called Krabbe disease. Aisenberg et al. define the molecular signature of disease-associated macrophages (globoid cells) and demonstrate that bra…
Immune-microbiota interactions are required to maintain host homeostasis. Kim et al. identified that steady-state sensing of IL-10 by interstitial macrophages (IMs) prevents spontaneous lung inflammation. In the absence of IL-10 signaling, microbial dy…
The local immunoregulatory mechanisms that safeguard the host from excessive lung infection inflammation remain unclear. Yeung, Yokota et al. uncover the essential role of nerve- and airway-associated macrophages (NAMs) in mitigating SARS-CoV-2 pathoge…
Liver regeneration (LR) is essential for recovery from acute trauma, cancer surgery, or transplantation. Fazel Modares et al. find that mouse LR after injury requires ChAT+ B cells synthesizing acetylcholine (ACh) and Kupffer cells and hepatic CD8+ T c…
The immune landscape of human and murine thrombosis remains unclear. Pekayvaz et al. map the immune landscape of thrombosis and describe prominent thrombolytic functions of immune cells, a pattern that they term immunothrombolysis: neutrophils recruite…
Glioblastoma is an aggressive subtype of glioma that responds poorly to immune checkpoint blockade (ICB). Galvez-Cancino et al. demonstrate that Treg cell depletion using a non-IL-2 blocking antibody—antiCD25NIB—activates CD8+ T cells and recruits FcγR…
Xiong et al. report that short-term, high-fat diet exposure rapidly alters the gut microbial and immune environment, disrupting tissue homeostasis. IL-22 production by group 3 innate lymphoid cells (ILC3s) is impaired, compromising gut barrier integrit…
Shen et al. show that A. faecalis induces intestinal Th17 cells under physiological conditions. A. faecalis proteins endocytosed by CD4+ T cells via CDC42 or OMVs prevent Trim21 self-ubiquitination degradation. Then, Trim21 enhances JunB-induced Ahr tr…
Mitochondrial dysfunction is a feature of cellular senescence. Lai et al. find that senescent tumor cells release mitochondrial (mt)DNA into the extracellular space, where it is taken up by PMN-MDSCs. Internalized mtDNA activates the cGAS-STING-NF-κB p…
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 neuroinflammat…
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 e…
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 …
Just a few weeks ago, researchers and educators connected to immunology lost a wonderful friend and colleague: Michael Cancro, professor of pathology and lab medicine at the University of Pennsylvania, passed away suddenly at his home just outside Phil…
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…
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 fi…
CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms. Immunological roles of sCTLA-4 are scarcely known. With mice deficient in either sCTLA-4 or mCTLA-4, Osaki et al. show that sCTLA-4, which is predominantly produced by Treg cells, suppres…
B cells that give rise to neutralizing antibody responses can be extremely rare in the naive B cell repertoire. Madden et al. show that delivery strategy and adjuvant selection affect the recruitment and expansion of rare broadly neutralizing antibody-…
by Jyothi N. Purushotham, Holly L. Lutz, Edyth Parker, Kristian G. Andersen
In this perspective, Andersen and colleagues examine how host immunity shapes the emergence, evolution, and persistence of novel and emerging viruses. They highlight the role of antibody-driven selection in viral adaptation and endemicity, emphasizing …
How tumor cells overcome anti-tumor immune responses and drive cancer recurrence is not well understood. Yu et al. demonstrate how therapy-resistant breast cancer cells synthesize and secrete arachidonic acid-rich lipids to reprogram tumor-infiltrating…
by Alexander J. Nelson, Bruna K. Tatematsu, Jordan R. Beach, Dorothy K. Sojka, Yee Ling Wu
IgE-expressing B cells fail to form memory B cells (MBCs). Nelson et al. show that inhaled allergen induces the formation of lung-resident MBCs with IgG1+ MBCs class switching to IgE driven by interleukin-4 from lung Th2 cells. Upon rechallenge, these …
Metallophilic marginal zone macrophages are positioned strategically within the spleen to process internalized blood-borne materials. Mauvais et al. find that these CD169+ macrophages cross-prime CD8+ T cell responses to internalized antigens using a p…
MEF2C is an essential immune checkpoint that prevents microglial overactivation, though its mechanisms remain elusive. Hu et al. reveal that MEF2C restrains microglial overactivation via modulating the p21-CDK2-RB-NFκB axis. In Mef2c-deficient mice, th…
Next-generation influenza vaccines aim to overcome the limitations of current seasonal vaccines and generate durable and broadly protective immunity against influenza by targeting conserved epitopes. Guthmiller et al. demonstrate that cHA vaccination e…
How glial cells change and impact ALS pathogenesis is unclear. Zelic et al. utilize single-nucleus RNA sequencing to identify disease-enriched glial inflammatory states and activation markers in ALS spinal cords. Using human tissue, iPSC-derived tri-cu…
Particle exposure drives inflammation through unknown regulatory mechanisms. Cobo et al. identified a bifurcated transcriptional response in macrophages: an AMPK-TFEB/TFE3-DNMT3A/DOT1L axis controlling lysosomal acidification and a JNK-AP-1 pathway dri…
by Xiaocui Luo, Xiaoxiao Hou, Yifeng Wang, Ye Li, Shangcheng Yu, Hai Qi
Memory B cells (MBCs) emerging from germinal centers (GCs) are crucial for antibody-based vaccines. Luo, Hou, et al. find that T cell-derived interleukin-9 promotes expression of the transcriptional repressor ZBTB18 in GC B cells. ZBTB18 represses the …
Central nervous system malignancies include primary tumors and brain metastases (BrMs) originating from extracranial cancers. Bejarano et al. examine primary and metastatic brain tumors and find distinct vascular alterations in IDH mutant gliomas, IDH …
VEGF blockade is known to enhance immune checkpoint blockade (ICB) efficacy, but its precise immunological mechanism remains undefined. Benmebarek et al. reveal that VEGF inhibition drives BAFF- and IL-12-dependent Treg reprogramming, promoting a fragi…
by Iona S. Schuster, Matthew E. Wikstrom, Christopher E. Andoniou, Mariapia A. Degli-Esposti
A 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) infec…
by Alba Llibre, Salih Kucuk, Atrayee Gope, Michelangelo Certo, Claudio Mauro
Lactate shows immunomodulatory properties. Mauro et al. review how lactate serves a fuel for the TCA cycle and an immunomodulatory molecule with context-dependent effects, and how its immunomodulatory properties are mediated via sensing through transpo…
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 f…
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 immunothe…
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 t…
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 SPe…
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 dea…
by Christin Friedrich, Tommaso Torcellan, Georg Gasteiger
In 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-ba…
Existing cancer immunotherapy target discovery platforms typically focus on a single cell type. Luo et al. develop ICRAFT, an interactive platform that integrates CRISPR screens and transcriptomic datasets to identify immunomodulatory gene targets acro…
NK cells possess innate and adaptive features, but unlike T and B cells, NK cells are not thought to require priming in lymphoid organs. Mujal et al. demonstrate that the spleen supports enhanced expansion of a CD69lo adaptive NK cell precursor populat…
Multiple exposures to an evolving virus can drive antibody affinity maturation toward cross-reactivity. How viruses continue to evolve despite these broad antibodies is unclear. Maurer et al. show that cross-reactive antibodies limit viral escape in th…
