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…
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…
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…
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 …
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 …
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 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…
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…
During chronic inflammation, regulatory T (Treg) cells fail to effectively control effector T cells due to unresolved mechanisms. Here, Neuwirth and Malzl et al. identify the polyamine catabolic enzyme SSAT as a key driver of Treg cell dysfunction, whi…
Circulating memory CD8+ T cells are thought to be highly dependent on interleukin (IL)-7 signaling. Using inducible Il7ra deletion in circulating and tissue-resident memory CD8+ T cell subsets, Jarjour et al. reveal resilience to loss of IL-7 signaling…
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…
To understand the influence and longevity of early influenza imprinting, Spangler et al. investigate the response to an H2 HA vaccine in individuals with and without exposure to H2N2 virus 50 years ago. They find that those with prior exposure have a r…
The pathogenesis of neonatal necrotizing enterocolitis (NEC) remains to be fully elucidated. Zhang et al. demonstrate that dysbiosis induces ferroptosis of intestinal epithelial cells via bile acid receptor FXR. This subsequently impairs IL-22 producti…
Members of the interleukin-17 family are associated with tumor progression in various settings. Denk et al. find that, in colorectal cancer, IL-17RA switches from tumor promotion during early tumorigenesis to tumor suppression during tumor invasion and…
Hypertensive heart disease, initially established as an adaptive response, might progress toward heart failure, and the nervous and immune systems participate in this process, but their interaction is unclear. Perrotta et al. identify a brain-body circ…
The polyclonal CD8+ T cell response to a single antigen is the average of several hundred individual T cell clonotypes. Abdullah et al. demonstrate that most clonotypes exhibit TCR-intrinsic differentiation biases toward memory or effector fates and ar…
Maintaining blood sterility during urinary tract infections is crucial for preventing urosepsis. Li et al. identify a subset of bladder-resident suburothelial perivascular macrophages that is essential for restricting systemic uropathogen dissemination…
by Wanwan Huai, Kun Yang, Cong Xing, Kun Song, Heng Lyu, Noelle S. Williams, Jianjun Wu, Nan Yan
Innate immune signaling pathways are traditionally considered to be intracellular. Huai et al. show that the RNA-sensing OAS-RNase L pathway can initiate in one cell and complete in another cell through the transfer of second messenger, 2-5A, acting as…
How innate immune signaling within neurons influences neurotransmission remains poorly understood. Estevez et al. show that the necroptotic kinase RIPK3 promotes neuronal survival during viral infections of the central nervous system by engaging a CaMK…
The enteric nervous system is a key regulator of inflammation, crosstalking directly with the immune system at the mucosal surfaces of the gastrointestinal tract. In this issue of Immunity, Wang and colleagues demonstrate that intrinsic enteric neurons…
Indirect CD4+ T cell indirect allorecognition of donor peptides presented by host MHC class II antigens contributes to transplant rejection in part by eliciting donor-specific antibodies (DSAs). In this issue of Immunity, Zhanzak et al. revisit the rol…
Renowned for driving interferon responses, the cGAS-STING pathway reveals a surprising role: lysosomal biogenesis. In this issue of Immunity, Xu et al. uncover how STING activates the transcription factor TFEB, linking innate immune sensing to enhanced…
Mechanisms that differentiate the capacity of newborn immune cells to orchestrate tissue regeneration are inadequately understood. Lantz et al. discover that in response to dying cells, neonatal macrophages synthesize and release pro-regenerative bioac…
Can bacteria that breach mucosal barriers drive long-lasting changes in immunity? In this issue of Immunity, Robles-Vera et al. describe how, in the context of colitis, bacteria breaching the intestinal barrier reprogram precursors in the bone marrow v…
In a recent work reported in Science, Zhang et al. untangle dynamic changes arising across aging in multiple cell populations within thirteen organs using single-cell transcriptomics and identify four distinct dynamic waves in which immune cells are th…
Generating genetically engineered mouse strains for in vivo studies can be a challenging and lengthy process. Nyberg, Wang, Ark, et al. present a method for gene transfer to mouse T cells in vivo using an evolved adeno-associated virus variant and demo…
Despite its range of disease associations, Epstein-Barr virus (EBV) treatments or vaccines are lacking. Joyce et al. determined EBV gp350 structures complexed with either its human receptor, CR2, or virus-neutralizing antibodies (nAbs), thus illustrati…
Jaschke and Wang review the current understanding of leukocyte compartmentalization in homeostasis and upon organismal stress, how neuroendocrine signals organize this trafficking, and the mechanisms underlying the functional diversification of leukocy…
How NLRP3 impacts Alzheimer’s disease (AD) is unclear. McManus et al. find that NLRP3 is located at mitochondria where it regulates microglial metabolism. Depletion or chronic pharmacological inhibition of NLRP3 increases glutamine utilization and α-ke…
Thymic injury leads to reduced T cell production and makes patients more vulnerable to infections and cancers. Lemarquis et al. identify a population of recirculating regulatory T (Treg) cells that mediate regeneration in the injured thymus, partially …
Recent studies highlight the role of neurons in regulating anti-helminth immune responses, suggesting that intrinsic enteric neurons (iENs) may orchestrate intestinal immunity. Wang and Zhang et al. show that iENs sense helminth infection-induced ILC2 …
The lack of well-defined indirect CD4+ T cell epitopes has hindered mechanistic studies and the development of antigen-specific tolerance strategies in transplantation. Zhanzak et al. identify donor-derived CD4+ T cell epitopes associated with rejectio…
Common genetic variants in a cis-regulatory element at HDAC9, which regulates expression of the histone deacetylase HDAC9, are a major risk factor for cardiovascular disease. Asare et al. define a mechanism whereby HDAC9 regulates activation of the NLR…
scRNA-seq has uncovered ontogenically distinct hepatic macrophage populations, but their functions remain unclear. Here, De Ponti et al. identify recruited LAMs and resident LAM-like KCs in multiple liver injury models and reveal that TREM2 expression …
Robles-Vera et al. unveil the capacity of gut microbiota translocation, particularly Enterococcus faecalis, to mediate a Mincle-dependent induction of trained immunity in myeloid bone marrow progenitors. This can be protective against subsequent infect…
Cryoglobulinemic vasculitis is a common complication of HCV infection. Young et al. reveal that three categories of somatic mutagenesis converge on a single B cell to generate pathogenic, autoantibody-producing clones in this virus-induced autoimmune d…
by Melissa Ng, Daniela Cerezo-Wallis, Lai Guan Ng, Andres Hidalgo
Far from homogeneous, neutrophils acquire remarkable diversity, particularly in the context of cancer. Ng, Cerezo-Wallis, Ng, and Hidalgo discuss the origin and mechanisms underlying the adaptation of neutrophils to cancer. They highlight intrinsic and…
by Shuangshuang Yang, Guannan Huang, Jenny P.-Y. Ting
Mitochondria play critical roles in intrinsic apoptosis and NLRP3 inflammasome activation, but how these processes are interconnected remains unclear. In this issue of Immunity, Saller et al. unveiled the complexity of NLRP3 activators, highlighting mi…
by Matthew C. Sinton, Olivia Shorthouse, Alice Costain, Juan F. Quintana
Interleukin-17 plays a major role in controlling adipose tissue homeostasis. In a recent study published in Nature, Douglas et al. demonstrate that time-of-day-dependent expression of interleukin-17 by tissue-resident innate lymphocytes in the adipose …
Ischemic stroke and vascular cognitive impairment are global health threats. Recent research has uncovered a previously underappreciated dynamic interplay between brain-resident, meningeal, and systemic immune cells. Iadecola and Anrather discuss the n…
Inhibiting T cell exhaustion is an attractive cancer immunotherapy strategy. In this issue of Immunity, Waibl Polania et al. examine the microenvironmental signals regulating terminal T cell exhaustion and find that antigen presentation by tumor-associ…
Immune activation during sustained stress typically worsens stress-related psychopathology. Whether it can enhance stress resilience remains unclear. In this issue of Immunity, Xia, Lu, Lan et al. uncover an anxiolytic function of intestinal IL-22 path…
The mechanisms underpinning susceptibility to influenza virus infection, resulting in life-threatening disease, are not well understood. In this issue of Immunity, Chakraborty et al. demonstrate that sialylated IgG suppresses NF-κB-driven inflammatory …
ABCC1 mediates the export of cGAMP, but the underlying molecular mechanism of cGAMP recognition and export is not clear. Here, Shinde et al. show that human ABCC1 forms a dimer in vitro and in vivo. Cryo-EM structures of ligand-free and cGAMP-bound ABC…
Interferon γ secretion by activated T cells alters the immunopeptidome landscape of cancer cells, enriching for W>F substitutant epitopes. Champagne et al. demonstrate that these induced neoepitopes are widespread, shared between cancer types, and are …
There are many dimensions to scientific life. We asked investigators about the impact of service to the scientific community and beyond and how service has shaped their experience, perspective, and research path.
How marginal zone B cells integrate cell-extrinsic and -intrinsic processes to achieve accelerated responsiveness is unclear. Allman et al. combined genetic and pharmacological approaches to establish how stromal Notch ligands control splenic B cell ho…
Thymic mimetic cells are chimeras between medullary-thymic-epithelial cells (mTECs) and peripheral cell types. Huisman, Michelson, et al. perform high-resolution profiling of human mimetics, revealing a diversification of nerve and ionocyte mTECs and a…
Aberrant immune signal strength in B cells is associated with autoimmune diseases and lymphoma. Diehl et al. show that hyperreactive B cells trigger cytotoxic T cell-mediated elimination. Less reactive B cells escape this tolerance mechanism, revealing…
The balance of T cells in a progenitor-exhausted state and those in a terminally exhausted state is a critical determinant of anti-tumor responses. Waibl Polania, Hoyt-Miggelbrink, et al. identify antigen presentation and tumor-associated macrophages (…
The intersection between cellular metabolism and innate immunity lacks understanding. Here, Rao and Qin et al. report that the metabolic enzyme, CTP synthetase 1, deamidates IRF3 to limit interferon induction, independent of its role in pyrimidine synt…
Depletion antibodies and genetically engineered mouse models are commonly used to investigate lymphocyte subsets in immunity, albeit with limitations. Kastner et al. develop adeno-associated viral vectors delivering depletion antibodies that eliminate …
Scott et al. combine migration assays, myriad infection models, and multi-omics to describe the broad adaptability of tissue-resident memory CD8+ T (Trm) cells to diverse stimulatory and environmental inputs. They report limitations in common proxy mar…
Human MR1-restricted cells may recognize target cells with altered metabolism, but their function and the nature of recognized self-antigens remain poorly defined. Chancellor et al. find that human MR1T cells recognize a carbonyl adduct of adenine, whi…
The cGAS-STING pathway induces autophagy to deliver cytoplasmic DNA and invading pathogens to lysosomes for elimination. However, whether lysosome function is regulated by the cGAS-STING pathway remains unknown. Xu et al. discover that the cGAS-STING p…
CD4+ T helper (Th) cell differentiation depends on regulatory networks that enforce lineage commitment while suppressing alternative fates. In a recent issue of Nature, Hou et al. reveal that calcitonin gene-related peptide (CGRP) directs Th1 commitmen…
Hidradenitis suppurativa (HS) is a severe chronic inflammatory disease without effective treatment options. Yu et al. identify and characterize tertiary lymphoid structures (TLSs) in HS, highlighting fibroblast-driven TLS formation via cytokine feedbac…
Despite protective roles in various type of infection and in would healing, T helper (Th)2 cells are drivers of inflammation in allergic asthma. In this issue of Immunity, Zou et al. demonstrate the crucial involvement of hypoxia inducible factor (HIF)…
by Thomas Plum, Thorsten B. Feyerabend, Hans-Reimer Rodewald
Mast cells act as “signal converters,” translating immunological and tissue signals into host-protective behaviors. They sense antigen and possibly toxins driving avoidance behavior, which can prevent inflammation and tissue damage. Beyond classical im…
Central tolerance restricts T cells that target self-antigens. In this issue of Immunity, Abdelfattah et al. describe a method to generate self-reactive T cell receptors (TCRs) by directed evolution of non-autoreactive TCRs to recognize self-antigen pe…
Rheumatoid arthritis (RA) is driven by antigen-specific T cell responses targeting the joints. MacDonald et al. define the range of dendritic cell (DC) populations within joints of RA patients and highlight specific iDC3 and DC2 populations enriched in…
Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease with limited response to therapy. In this issue of Immunity, Yu et al. identify skin tertiary lymphoid structures (TLSs) as primary sites for lymphocyte clonal expansion and au…
Inpp5d, which encodes the lipid phosphatase SHIP1, is a risk gene for Alzheimer’s disease, but its role in brain development has been poorly studied. Matera, Compagnion et al. demonstrate that Inpp5d is expressed in microglia during early postnatal bra…
Immune activation is often thought to exacerbate stress-related mental disorders. Here, Xia, Lu, Lan, et al. reveal elevated IL-22 derived from the gut during the early phase of repeated stress. IL-22 suppresses neuron activation in the brain and mitig…
by Nouran S. Abdelfattah, Tomasz Kula, Stephen J. Elledge
Abdelfattah et al. developed an engineering platform (T-Switch) for the creation, modification, and high-throughput profiling of T cell receptors (TCRs) to desired targets, particularly self-antigens. T-Switch identified potent and specific candidate T…
The nature of B cell priming determines PC formation, affinity maturation, and long-lasting immunity. Faliti et al. demonstrate that IL-2, a key T helper cell cytokine, acts intrinsically on B cells to trigger a “vanguard” metabolic shift that activate…
The relationship between antigen recognition and HIV-1 gene expression is unclear. Moskovjlevic et al. reveal that CD4+ T cell antigen recognition can drive HIV-1 transcription in individuals on ART. Antigen presentation induces T cell activation and p…
How dendritic cells (DCs) regulate human tissue immunity remains unclear. MacDonald, Elmesmari, Somma, Frew, et al. investigate the role of synovial tissue (ST) myeloid DCs in health and active and remission stages of rheumatoid arthritis. Using a comb…
T helper (Th) 2 cells can exert protective or pathogenic roles, depending on challenge or disease context. Zou et al. examine the heterogeneity of Th2 cells in type II inflammation in humans and mice and demonstrate a critical role for HIF2α in driving…
CAR-T cells form disorganized immunological synapses. Xu et al. find that incorporation of the CD3ε module into CAR induces liquid-liquid phase separation, promoting the formation of mature immunological synapse with integrated antigen and costimulator…
Ogishi, Kitaoka, et al. examine humans deficient in PD-1 and PD-L1 as well as associated mouse models and find that PD-1 and PD-L1 promote B cell memory and antibody responses through both T cell-dependent and B cell-intrinsic mechanisms. Their finding…
Overexpression of transposable elements is a common feature of cancer. Sun, You, et al. show that, in pancreatic ductal adenocarcinoma, tumor cells adapt through different mechanisms to mitigate a specific group of dsRNA-producing repeats in a TP53-dep…
Through an in vivo Rainbow-CRISPR screen, Wang et al. systematically assess the roles of each of 35 nuclear receptors (NRs) across the immune system, revealing focal, cell-specific involvements as well as noncanonical functions. In cavity macrophages, …
Mitochondria control metabolism, cell death, and innate immunity, yet their reciprocal mechanistic connections are elusive, as is the conserved physiological function of the NLRP3 inflammasome. Saller et al. reveal that inhibition of mitochondrial ATP …
MHC class I interactions with different immune receptors can mediate either activating or inhibitory functions. Tsao, Anderson, Finn, et al. show that loss of ERAP, the aminopeptidase that trims peptides for presentation on MHC class I, enhances immune…
Several recent studies have demonstrated that B cell targeting chimeric antigen receptor (CAR) T cells offer a viable treatment option for patients with autoantibody-mediated autoimmune diseases. In this report, we summarize recent findings and key dev…
