Neuroinflammation contributes to Alzheimer’s disease (AD), but the molecules and pathways that initiate inflammation are unclear. In this issue of Immunity, Song et al. demonstrate that ZBP1-RIPK1 signaling in microglia can drive AD, wherein ZBP1 is ac…
Upon activation, individual CD8+ clones decide between effector and memory T cell fates by integrating intrinsic T cell receptor (TCR) signals or “nature” and extrinsic signals from co-stimulatory ligands and inflammatory cytokines or “nurture”. The co…
Fibroblasts and immune cells robustly respond to brain injuries and form a persistent “scar.” In a recent issue of Nature, Ewing-Crystal et al. report that fibroblasts have dynamic states that modulate neuroinflammatory responses to brain injury, vital…
Vaccines that induce immunity in tissues are urgently needed. In this issue of Immunity, Joag et al. demonstrate that systemic vaccination of primates induces tissue-resident CD8+ T cells in numerous organs that can activate antiviral responses by stro…
T cells need reactive oxygen species (ROS) for activation and memory formation, yet excessive ROS can drive dysfunction. Rivadeneira et al. show that chronic T cell activation in tumors exposes telomeres to damaging mitochondrial ROS, contributing to T…
Membrane targeting and pore formation of gasdermin C are facilitated by its proteolytic cleavage. In this issue of Immunity, Pandey et al. show how cathepsin S cleaves intestinal epithelial gasdermin C to amplify type 2 immune responses.
by Adrian Straub, Zahra Abedi, Dirk H. Busch, Veit R. Buchholz
Abdullah et al.1 recently set out to gauge the influence of T cell receptor (TCR)-intrinsic vs. -extrinsic factors on memory vs. effector fate decisions of CD8+ T cells. They concluded that “a majority of TCR clonotypes were highly biased toward memory…
CD8+ resident memory T (Trm) cells surveil tissues, acting as frontline sentinels of infection. Joag et al. find that, in primates, systemic vaccination promotes a Trm cell response in barrier compartments, where Trm cells conscript neighboring cells w…
Cardiovascular risk factors can spark inflammation by eliciting misdirected responses of intrinsic vascular cells and leukocytes, culminating in lesion initiation, progression, and complication. Soehnlein and Libby review key underlying inflammatory me…
Obesity and its related disorders are now recognized as chronic inflammatory conditions. Donath and Drucker review the mechanisms underlying inflammation in these settings and discuss how understanding the mechanisms whereby Glucagon-like peptide-1 (GL…
TCF-1, encoded by Tcf7, supports CD8+ T cell memory and is silenced in effector T cells. Murphy et al. identify two cis-elements required for Blimp1-mediated Tcf7 repression and find that decoupling Tcf7 silencing from effector differentiation is permi…
Metabolic stress imposed by the tumor microenvironment (TME) promotes T cell dysfunction and limits antitumor immunity. Alicea Pauneto et al. demonstrate the hypoxia within the TME drives chronic activation of ATF4, which promotes metabolic polarity an…
Polletti et al. show that in macrophages, ISWI chromatin remodelers preserve nucleosome arrays flanking PU.1-bound sites. ISWI deficiency enabled binding of the transcriptional regulator C/EBPβ to non-myeloid genomic regulatory elements, driving lineag…
Chronic rhinosinusitis (CRS) is driven by poorly understood immune-epithelial crosstalk. Liao et al. present a single-cell and spatial transcriptomic atlas of CRS, revealing how immune and epithelial cells interact to drive tissue remodeling and inflam…
The functional state of tumor-infiltrating lymphocytes is a critical determinant of antitumor immunity and response to immunotherapy. Rivadeneira et al. demonstrate that mitochondrial ROS accumulation induces oxidative damage at telomeres, which is suf…
by Eran Elinav, Lilach Agemy, Dinorah Friedmann-Morvinski
Dr. Zelig Eshhar, a professor of immunology at the Weizmann Institute of Science and head of immunology research at the Tel Aviv Sourasky Medical Center, passed away on July 3, 2025, at the age of 84. Zelig was best known as the pioneer of chimeric ant…
Clinical and therapeutic innovation relies on our understanding of the human immune system. Here, investigators discuss current and developing methodologies to study human immunity, and the importance of thoughtful experimental design and sample collec…
In a recent issue of Nature, Adrover et al. report a neutrophil subset that induces pleomorphic tumor necrosis through NET-mediated vascular occlusion. This process drives epithelial-to-mesenchymal transition and metastasis of perinecrotic cancer cells…
Wang et al. demonstrate that gut rather than skin microbiota promote skin inflammation in a spontaneous psoriasis mouse model by fueling the production of the metabolite indoxyl sulfate (I3S). I3S amplifies Th17-mediated skin inflammation via AHR-depen…
The immune system of wildlings—mice with a wild-derived microbiota—has features similar to that in adult humans. In this issue of Immunity, Oh et al. demonstrate the long-term stability of wildling microbiota and immune traits, establishing these mice …
In this issue of Immunity, Lv et al. develop a new CAR-T cell culture system that uses integrin mechanical signaling to boost CAR-T proliferation while preserving stemness, pointing out a new direction of CAR-T manufacturing.
The small intestine coordinates nutrient absorption and immune defense, but the epithelial signaling mechanisms bridging these functions are unclear. In this issue of Immunity, Yu et al. reveal a gasdermin-D-driven circuit that links lipid uptake and e…
Specialized macrophages are known to persist within tissue niches, but the molecular mechanisms guiding their sustained functional adaptation remain unclear. Kolter and Döring et al. show that local interactions between sensory nerves and macrophages a…
Microglia-mediated neuroinflammation drives Alzheimer’s disease (AD) pathogenesis, yet the underlying mechanism is poorly understood. Song et al. demonstrate that toxic amyloid-β induces oxidation and fragmentation of mitochondrial DNA in microglia, fa…
Pregnancy-induced microchimerism is linked with both inflammatory disorders and immune tolerance phenotypes. Peng et al. develop a platform for lineage-specific microchimeric cell depletion and show that tolerance to non-inherited maternal antigens is …
Transcription factors are known to guide dendritic cell identity, but how they cooperate to drive lineage diversification remains unclear. Henriques-Oliveira, Altman, Kurochkin, et al. identify two transcription factor triads that remodel chromatin and…
The transporter associated with antigen processing (TAP) delivers peptide antigens from the cytoplasm into the endoplasmic reticulum for loading onto MHC-I molecules. Lee et al. generate cryo-electron microscopy structures of the human TAP heterodimer …
Inflammatory bowel disease is a multifactorial disease driven by combinations of susceptibility factors. Kaya et al. demonstrate how XBP1 deficiency impairs MUC2-mediated mucus barrier formation. Diminished mucus formation synergizes with epithelial ce…
Andersen et al. report the immunopathogenesis of severe H5N1 avian influenza virus clade 2.3.4.4b infection in cynomolgus and rhesus macaques. Inflammation and immune dysregulation were key mechanistic pathways of H5N1 influenza pathogenesis in nonhuma…
Chemokines are essential signals that coordinate immune responses, yet how they are organized in time and space to convey information remains incompletely understood. Xi et al. develop a genetically encoded CXCL10 sensor, LoX3-1.0, to visualize the sta…
How various tumoral metabolites impact antitumor T cell immunity is an area of active research. Ma et al. demonstrate that succinate enhances mitochondrial fitness and induces epigenetic reprogramming to promote CD8+ T cell stemness, thereby augmenting…
Tumor cells utilize macropinocytosis to acquire nutrients to survive, but the role and metabolic regulation of tumor cell macropinocytosis in immune escape remain unclear. Wang et al. identify dihydroorotate dehydrogenase (DHODH) as being required for …
In the letter to Immunity, Morris et al.1 discuss the possible regulatory mechanism of phospholipid phosphate phosphatase 1 (PLPP1) in CD8+ T cell activity. Here, we conduct an in-depth analysis of our work and other published studies, identifying pote…
Regulatory T (Treg) cells maintain immune and tissue homeostasis. In this issue of Immunity, Bündgen et al. find that intratumoral polyamines promote immunosuppressive Treg cells via CK2. Targeting the polyamine-CK2 axis shifts Treg cells to become tis…
Pulmonary immunity must strike a precise balance between protecting the delicate mucosal tissue from environmental threats and preserving its vital gas-exchange function. In this issue of Immunity, Li et al. and Hiroki et al. illuminate how the nervous…
ICOS agonists are being investigated for cancer immunotherapy based on the idea that they will reinvigorate exhausted CD8+ T cell anti-cancer immunity. Humblin et al. unexpectedly find the opposite—that CD8+ T cell-intrinsic ICOS expression restrains r…
The “Christchurch” protective variant in the APOE gene has recently been identified, but its mechanisms of action remain unknown. In this issue of Immunity, Naguib and Lopez-Lee et al. provide evidence for the APOE-Christchurch variant suppressing micr…
by Hai Qi, Mark M. Davis, Carola Vinuesa, Laura K. Mackay
Understanding fundamental lymphocyte biology and developing innovative strategies to harness lymphocytes to treat human diseases were the themes of the first SMART Symposium in Immunology held in March 2025 in Shenzhen, China.
Phospholipids regulate immune cell functions through both intracellular and extracellular mechanisms, engaging lipid-modifying enzymes, cell surface receptors, and lipid mediators such as lysophosphatidic acid (LPA), sphingosine 1-phosphate, and prosta…
CAR T cell therapy in solid tumors remains challenging. Lv et al. report that 3D fibrin gel-generated mechanical signaling separates the proliferation and differentiation programs. This allows for robust expansion of stem-like CAR T cells, which infilt…
Mitochondrial reactive oxygen species (mtROS) serve as critical signaling molecules that regulate immunity. Chandel et al. review the spectrum of mtROS effects, ranging from essential roles in innate immune activation and T cell differentiation to path…
Neutrophils are highly dynamic immune cells with diverse phenotypes shaped by development, tissue-specific signals, and disease contexts. This perspective proposes a four-tiered framework integrating maturation, tissue localization, and function to sta…
Mutations in MLL3, encoding the histone methyltransferase MLL3/KMT2C, are frequent in various cancer types. Boutet, Nishitani, et al. show that the loss of MLL3 stabilizes HIF1α, which induces expression of the chemokine CCL2 and promotes infiltration …
Vasandan et al. leverage a gene therapy study of X-linked severe combined immunodeficient individuals to longitudinally examine human immune development. They find early emergence of antigen-independent, innate-like memory T cells that are epigenetical…
Bündgen et al. reveal that polyamines in the tumor environment shift Treg cells toward suppression via CK2 signaling. Blocking this pathway reprograms Treg cells to support tissue repair and antitumor immunity. These findings highlight a potential stra…
Human memory T cells persist in tissues as circulating and tissue-resident populations. Lam et al. reveal asynchronous aging of T cells across sites and subsets. Splenic memory T cells are longer-lived compared with mucosal sites and blood. Tissue-resi…
The transfer of microbiota and pathogens from wild mice to genetically tractable laboratory mice has been shown to enhance modeling of human immune responses in preclinical studies. However, the long-term stability of the transferred complex microbiota…
Precisely how diet regulates intestinal immunity and barrier function remains underexplored. Yu et al. identify a link between nutrient signals and host defense directed by diet-induced, GSDMD-mediated epithelial-immune co-adaptation. This study contri…
Pandey et al. identify Cathepsin S (CTSS) as the direct protease that cleaves Gasdermin C (GsdmC) in the intestine. Type 2 immune-promoting microbes trigger CTSS-dependent GsdmC activation in intestinal epithelial cells, targeting Rab7+ vesicles, alter…
Upon pathogen detection, phagocytes trigger immunity. This process induces tissue stress and the formation of host-derived molecules that further tune immune responses. We show that host-derived oxidized phospholipids accumulate upon microbial encounte…
Physical cellular interactions are crucial yet remain challenging to investigate in vivo. Deng et al. develop CINTER-seq, a chemical tool enabling in situ capture and multimodal profiling of interacting cells in living mice, uncovering specific LAG3-MH…
by Yan Wang, Di Xu, Shaorui Liu, Haoyang Li, Yinsheng Wang, Hui Li, Heping Xu, Danyang He
The brain meninges maintain self-tolerized B cells, but the pathological consequences of breaking this tolerance are unknown. Wang et al. reveal that autoreactive leptomeningeal B cells drive neuroinflammation by engaging pathogenic T cells and amplify…
While the immune response to Plasmodium falciparum malaria has been studied extensively, the circulating proteome and its cellular origins remain poorly characterized. Lautenbach et al. address this by integrating plasma proteomics and single-cell RNA-…
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…
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 …
Understanding regulation of progenitor exhausted CD8+ T (Tpex) cell differentiation is important for immunotherapies. Humblin et al. report that sustained ICOS costimulation is detrimental to PD-1+CD8+ T cell responses. Limiting ICOS signaling enhances…
While neurons and microglia are known to talk to one another, the signals that regulate their complex, important interactions are not comprehensively defined. Devlin et al. find that the cytokine IL-34 produced by excitatory neurons instructs the devel…
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 …
The APOE3 Christchurch mutation (R136S) reduces tau pathology despite the PSEN1 mutation and high amyloid, though its protective mechanism remains unclear. Naguib et al. show that R136S suppresses microglial cGAS-STING-IFN signaling in tauopathy mice. …
While BCG is the standard therapy for bladder cancer, its clinical limitations demand improved strategies. Jurado et al. show that combining BCG with β-glucan reprograms granulopoiesis to generate trained neutrophils with enhanced antitumoral activity,…
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…
The impact of risk factors for severe infections (being old, male, obese, and having comorbidities) on immune dysregulation prior to infection remains understudied. Using 12,026 blood samples, Ganesan et al. showed that their previously described 42-ge…
Although autoreactive CD8+ T cells kill melanocytes in vitiligo, the underlying mechanisms remain elusive, and effective therapeutic drugs are lacking. Yang et al. reveal that nociceptor-derived CGRP strengthens cDC1-CD8+ T cell interactions, leading t…
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…
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…
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 …
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…
Listeria monocytogenes (Lm) cancer vaccines have variable efficacy. Garcia Castillo, Fernandez, Campbell, et al. show that intratumoral Lm can either enhance or inhibit tumor progression, with tumor control depending on the presence of CD8+ T cells tar…
Severe pneumonia is predominantly caused by cytokine storms in the lung, but how this process is controlled remains unclear. Li et al. find that severe pneumonia activates central amygdala GABAergic neurons, which triggers a sympathetic nerve-pulmonary…
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…
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…
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…
Sensory innervation impacts several lung diseases, but whether it influences pulmonary fibrosis (PF) is unclear. Hiroki et al. report that depletion of TRPV1+ nociceptors leads to worsening of inflammation-induced PF. Mechanistically, nociceptor deplet…
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…
