Powerful interferon (IFN)-I-producing capacity distinguishes plasmacytoid dendritic cells (pDCs) from related innate cells. Adams et al. find that, during pDC development, the locus encoding IFN-I genes acquires a unique intranuclear localization and c…
Type 1 conventional dendritic cells (cDC1s) are key antigen-presenting cells and have been implicated in the induction of peripheral tolerance, yet how cDC1s actively enforce immune tolerance remains unclear. In a recent issue of Nature, Zhang et al. p…
Defining the antigen specificity of T cell receptors (TCRs) remains a significant barrier to understanding adaptive immunity in various pathologies. In this issue of Immunity, Gaglione et al. report the development of TCRAFT, a novel platform that enab…
Immunotherapeutic approaches to brain aging remain largely preclinical and in early translational stages, and they have focused mostly on modulating innate immunity. In this issue of Immunity, Negredo et al. identify T cells bearing exhaustion-like sig…
Tissue inflammation introduces unique, and often harsh, environments for immune cells. During allergic airway inflammation, pathogenic ILC2s proliferate robustly and drive pathology, but how do they overcome the nutrient-depleted environment? In this i…
Microglia display remarkable plasticity, with their cellular states evolving in response to developmental stage, regional context, and environmental or pathological stimuli. In this issue of Immunity, Hamagami et al. demonstrate that adaptive reconfigu…
The function of the Alzheimer’s disease (AD) risk gene INPP5D in microglia remains unclear. Xie et al. identify INPP5D as a direct regulator of RIPK1 kinase, known to be implicated in mediating neuroinflammation. They show that INPP5D deficiency in agi…
Adaptive programming in lymphocytes during infection depends on when—not just whether—they sense antigen and proinflammatory cytokines such as IL-12. Grassmann et al. reveal that AP-1/STAT4 cooperation links signal timing to lymphocyte fate, tuning CD8…
Meningeal B cells are increasingly recognized as active players at the brain border. Chen and Xu review recent advances in understanding their heterogeneity, developmental origins, spatial organization, and diverse functions in health and disease, and …
The recent transmission of highly pathogenic avian influenza A virus H5N1 from cattle to humans underscores its pandemic risk. Daniel, Ullrich, et al. reveal that H5-naive individuals possess low but detectable H5-reactive and neutralizing IgG antibodi…
Immune cells populate the old brain, but whether they can be specifically targeted to improve brain function in older individuals remains unclear. Navarro Negredo et al. dissect how aging impacts brain immune activity and show that targeting immune cel…
B cells transiently increase interleukin (IL)-2 receptor expression upon activation. Gauthier et al. examine the B cell-intrinsic role of IL-2 and define an IL-2-MAF axis that promotes the differentiation of CD25+ age-associated B cells toward a regula…
Dhariwala et al. demonstrate that commensal microbes recruit classical monocytes to neonatal skin. Disrupting this interaction triggers aberrant IL-17 secretion from cutaneous T lymphocytes, heightening risk of skin inflammation. IL-1 signaling in skin…
Mapping TCRs to antigens at scale presents a major challenge. Gaglione et al. develop an approach to rapidly synthesize and screen thousands of TCRs, enabling broad TCR-antigen screening. Examining T cell specificity in vitiligo uncovers autoreactive T…
Cytosolic nucleic acid sensors contribute to pathogenic and autoinflammatory inflammation; however, little is known about the metabolic adaptations that they induce. Dunphy et al. find that these pathways induce type I interferon-dependent metabolic ch…
Tumor-associated macrophages (TAMs) enhance cancer progression by driving angiogenesis, extracellular matrix remodeling, and immune suppression, yet their impact on nerve growth is unclear. Dolci and colleagues show that TAMs directly stimulate neurite…
by Xiu Zhong, Ya Su, Zhiwei Zhou, Yuqiu Sun, Yanjie Hou, Feng Shao, Jingjin Ding
In cellular immunity, cytotoxic lymphocytes-derived granzyme A (GZMA) targets the pore-forming protein GSDMB in target cells to confer pyroptotic killing, but how GZMA specifically recognizes and cleaves GSDMB is unknown. Zhong et al. demonstrate that …
The incidence of colorectal cancer (CRC) is elevated in individuals with inflammatory bowel disease. Pires et al. find that the cytokine TL1A stimulates production of GM-CSF by ILC3s, which triggers emergency granulopoiesis and neutrophil recruitment a…
Commensal microbes shape host immunity at barrier tissues and promote resistance to infection. Xu et al. identify a commensal Corynebacterium-derived lipid that activates IL-17⁺ γδ T cells via T cell receptor and IL-1 signaling, enhancing barrier defen…
IL-9 is canonically associated with anti-helminth and allergic immunity. However, in this issue of Immunity, Jiang et al. and Castelli et al. demonstrate how integrating IL-9 signaling in T cells enhances their persistence and anti-tumor function in so…
Regulatory T (Treg) cells suppress immune responses and are considered a major barrier to productive anti-tumor immunity. In this issue of Immunity, Huang et al. report that interleukin (IL)-10-producing Treg cells restrain tumor growth by suppressing …
Immune cells from the skull marrow reach the meninges through bone channels. In this issue of Immunity, Eme-Scolan and colleagues show that these channels form neonatally and can be remodeled to alter immune access to the brain’s borders. Their work su…
A long-standing debate in the field asks whether resident tissue macrophages are terminally differentiated or remain capable of changing their fate and function during inflammation. In this issue of Immunity, Verwaerde et al. uncover an IRF4-driven cir…
Ontogeny is a crucial determinant of macrophage function, but it remains unclear how a shared set of transcription factors generate distinct transcriptional programs across macrophage lineages. In this issue of Immunity, Chen et al. discover a transcri…
The water you touch in a river is the last of that which has passed and the first of that which is coming. Thus it is with time present.—Leonardo da Vinci
Microglia adopt diverse states throughout life. Whether these represent fixed lineages or reversible plasticity remains unclear. Hamagami and Kapadia et al. show that reactive microglia switch states through reprogramming of histone modifications at st…
Contemporary immunology research commonly utilizes detailed analyses of immunoglobulin sequences; however, IG immunogenetics remain understudied in rhesus macaques (RMs). Peres et al. combine IG genomic and repertoire sequencing of >100 RMs to provide …
Lucas et al. evaluate the interferon-gamma (IFN-γ) signature against toxicity and efficacy in four neoadjuvant melanoma immunotherapy regimens. IFN-γ-high scores associated with overall favorable efficacy but increased toxicity when anti-CTLA-4 was add…
by Hassan Jamaleddine, Bryan T. Grenfell, Andrea L. Graham, Judith N. Mandl
Mandl and colleagues describe an important gap in our understanding of how antiviral immune mechanisms in individual hosts alter the evolutionary trajectories of viruses as they spread through populations. They propose that bold new experimental system…
Skull marrow communicates with the meninges through bone channels, yet their formation and regulation remain poorly understood. Eme-Scolan et al. show that these channels undergo active remodeling during the neonatal period and can be reshaped by modul…
How distinct hematopoietic waves generate specialized macrophage lineages remains unclear. Chen et al. identify separate transcriptional pathways controlling macrophage development during primitive versus definitive hematopoiesis and identify Maf and J…
CCR7+ dendritic cells (DCs) are pivotal for antitumor immunity. Zitti, Duval et al. find that intratumoral CCR7+ DCs form perivascular hubs dependent on CCL19-CCR7 signaling. Regulatory T cells (Tregs) restrain immune function within these hubs, and bo…
Huang et al. study the heterogeneity of regulatory T (Treg) cells in a genetic model of colorectal cancer (CRC) and find that interleukin (IL)-10− Treg cells promote tumor progression, whereas IL-10+ Treg cells restrain tumor growth by suppressing IL-1…
Monocyte-derived macrophages are highly plastic, whereas tissue-resident macrophages resist inflammatory reprogramming. Verwaerde et al. show that tissue-resident alveolar macrophages can be reprogrammed during type 2 pulmonary immune responses by acti…
Immune cells must modulate their metabolism to adapt to tissue constraints. Wientjens et al. show that allergen-induced ILC2s and Th2 cells require cysteine-driven glutathione synthesis to prevent ferroptosis and support lipid metabolism. This redox ba…
by Xiaoxue Li, Wenhua Liang, Weifang Wang, Eilon Sherman, Keling Huang, Feng Wang
Blocking pathogenic T cell migration is crucial for treating autoimmune diseases. Li et al. reveal SUB1 as a gatekeeper of CD4+ T cell infiltration in autoimmunity. TCR-induced SUB1 drives Rac-dependent cytoskeletal remodeling via DOCK2 transcriptional…
Lung-resident memory CD8+ T cells coordinate rapid antiviral defense mechanisms across lung compartments to quicky limit viral replication and spread. In this issue of Immunity, Mattingly et al. demonstrate the importance of CD8+ Trm cell-derived inter…
Tumor necrosis factor (TNF), type I interferons (IFNs), and autophagy are important biological processes, but their interactions in inflammation have not been explored. In this issue of Immunity, Priem et al. reveal that ATG9A-mediated autophagy curbs …
TET2 mutations can drive clonal hematopoiesis (CH), but their impact on tumor immunity remains unresolved. Recently in Cancer Cell, Herbrich et al. reported that TET2-mutant CH reprograms tumor-associated macrophages to enhance antigen presentation and…
by Christophe Benoist, Dario A.A. Vignali, Richard A. Flavell, Diane Mathis
The seminal discoveries that established the role of regulatory T cells in immunological tolerance were recognized by this year’s Nobel Prize in Physiology or Medicine. Benoist and colleagues discuss the unfolding of the Treg story, the players involve…
The initial responses of microglia to neuronal stress or altered network activity are poorly characterized. Xie and colleagues show that during TDP-43-related neurodegeneration, microglia detect early neuronal hyperactivity and transition into a distin…
IgA plasma cells are the most abundant antibody-secreting reservoir in the body, yet details of their origin and behavior remain elusive. In this issue of Immunity, Simons et al. and Siniscalco et al. offer insights into IgA plasma cell dynamics during…
Systemic rotavirus infection poses a significant health challenge in neonates, but its underlying pathogenesis remains unclear. Xu et al. demonstrate that hepcidin-iron dysregulation in hepatic macrophages, particularly TREM2+ macrophages and Kupffer c…
While the phospholipid PI4P is implicated in STING activation, its molecular mechanism has remained elusive. Han et al. reveal that PI4P cooperates with the transmembrane agonist GNE-6468 to activate the STING immune response, highlighting its therapeu…
Our current understanding of microbial-host communication is largely based on context-dependent examples and anecdotes. Yamada and Palm present a teleological framework that organizes microbial metabolites based on their impacts on the host. These fund…
Gut plasma cells secrete IgA, which prevents infections, neutralizes toxins, and regulates the gut microbiota. Simons et al. demonstrate that stable IgA production results not from the persistence of individual plasma cells but rather a continuous dyna…
Memory is a central feature of the adaptive immunity. Saha et al. quantitatively model humoral memory and find that the pattern of waning of antibodies is better described by a power-law model rather than models with exponential waning. Their findings …
Human T cell responses are often studied using blood, yet most T cells reside in tissues. By comparing T cell receptor repertoires from millions of T cells from autologous tonsils and blood, Sureshchandra et al. demonstrate limited clonal, phenotypic, …
Mattingly et al. use human lung cells to show that virus-specific CD8+ tissue-resident memory T cells trigger epithelial antiviral defenses via IFNγ. This early protective response varies by epithelial subset, restricts influenza infection, and highlig…
Donor-specific antibodies against mismatched HLA proteins cause allograft failure, but the structural epitopes recognized by these antibodies are not well defined. Killian et al. identify immunodominant HLA-A∗01:01 epitopes that are localized specifica…
Castelli et al. show that incorporating interleukin-9 (IL-9) signaling reprograms chimeric antigen receptor (CAR) T cells to expand, persist, and resist dysfunction in solid tumors. This strategy improves antitumor activity at lower doses, suggesting a…
Cytokines optimize and fine-tune effector T cell responses. Here, Jiang et al. utilize IL-9, with scarce receptor expression in normal tissues, to boost IL-9R engineered T cells for cancer therapy. IL-9 signaling initiates a unique STAT activation patt…
IgA antibodies protect mucosal surfaces from foreign antigens. Siniscalco et al. identify germinal center (GC)-independent and GC-derived pathways of gut IgA generation following immunization. Siniscalco et al. also identify IgA generation from IgG1 pr…
FOXP3 is a transcription factor critical for immune homeostasis. Using a broad CRISPR toolkit, Umhoefer et al. elucidate the cis- and trans-regulatory circuitry governing FOXP3 expression in human Treg and Tconv cells, including characterization of a r…
Immunosuppressive monocyte-derived macrophages are key targets in cancer therapy; however, the mechanisms of their replenishment and functional plasticity remain elusive. In a recent issue of Nature, Hedge et al. challenge the conventional view that im…
Gut microbial metabolites modulate immune responses to tumors. In this issue of Immunity, Bachem et al. demonstrate that microbiota-derived butyrate cooperates with the transcription factor Foxo1 to promote CD8+ T cell stemness and enhance responsivene…
Sympathetic signaling has been implicated in colitis, but the precise circuits remain unclear. In this issue of Immunity, Sharma et al. demonstrate that myeloid cell-specific loss of DNA-demethylation dampens sympathetic signaling-driven colitis exacer…
Regulatory T cells can play conflicting roles in autoimmune inflammation. In this issue of Immunity, Benamar et al. reveal that gut-microbiota-induced Notch3+ regulatory T cells migrate to the central nervous system in multiple sclerosis and transition…
Until recently, the existence of long-lived IgE-secreting plasma cells was debated. Using timestamping in mouse models of type 2 inflammation, two studies in this issue of Immunity reveal the long-term persistence of IgE-secreting plasma cells in secon…
Time marches endlessly on … but what does that mean for the immune system? Here, investigators discuss how aging impacts the immune response and how immune cells can shape the aging process, with broader implications for modifying immunity to improve n…
The dynamics of antigen-specific Tfh responses during extended germinal center reactions are not well characterized. Marina-Zárate et al. show that vaccine-specific Tfh cells in the lymph node undergo robust early expansion, sustained proliferative cap…
Ding et al. show that allergy-associated IgE plasma cells exhibit limited accrual in the bone marrow, instead residing in other tissues for extended periods. These long-lived cells are rare and sensitive to navitoclax rather than deletion of the anti-a…
Using a mouse model that selectively lacks TET2 in myeloid cells, Sharma et al. show that myeloid cells and sympathetic neurons form a signaling nexus that controls serotonin production by enterochromaffin cells, which modulates colonic inflammation. F…
The gut microbiome impacts immunity at various levels, including response to immunotherapy. Bachem et al. find that metabolic pathways shared across different microbiota constituents, including SCFA synthesis, modulate stem-like tumor-specific CD127+CD…
David Baltimore, one of modern biology’s most influential scientists, passed away at his home in Woods Hole, Massachusetts, on September 6, 2025 at the age of 87, leaving legions of former trainees and the scientific community to contemplate the signif…
Bi et al. describe cell-type-specific transcriptional signatures of interferon (IFN) signaling in renal cell carcinoma (RCC) tumors and examine effects on immunotherapy outcomes. They find that myeloid IFNγ signaling, but not tumor IFNγ signaling, pred…
Cancers initially responsive to immune checkpoint inhibitors (ICIs) often relapse, and localized cancers can recur after surgery plus adjuvant ICI therapy. Wu et al. find that relapsing and recurrent melanomas evolve permutations of DNA copy-number var…
Wang et al. find that cell membrane stress upon viral infection induces expression and stabilization of host sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), which, in turn, degrades cGAMP to suppress cGAS-STING signaling and promote viral repli…
by Marina Terekhova, Pavla Bohacova, Maxim N. Artyomov
Artyomov and colleagues provide an overview of studies on age-related changes in the human immune system, from early flow cytometry research to more recent findings using single-cell and advanced cytometry methods. They explore possible sources of disc…
Allergies can persist even in the absence of allergen exposure. Miranda-Waldetario et al. find that IgE-producing plasma cells mature, acquire survival adaptations, and persist for extended periods of time in the spleen and bone marrow, secreting antib…
Memory CD8+ T cells can undergo TCR-dependent or -independent activation. Here, Lee et al. show that IL-15-induced bystander activation of human memory CD8+ T cells is suppressed by concurrent TCR signaling through NFATc1-AP-1 interactions. Furthermore…
Understanding the mechanisms underlying innate lymphoid cell (ILC) specification may provide insight into ILC functions in immunity and tissue homeostasis. Léger et al. demonstrate that NFIL3 expression in multipotent lymphoid progenitors is necessary …
The mechanisms sustaining the persistence of compartmentalized inflammation in MS remain unclear. By generating a spatially resolved single-cell atlas of chronic active MS lesions, Feng et al. reveal CD8+ T cell niches that are enriched with inflamed m…
Gliomas respond poorly to therapy and are considered immunologically “cold” tumors. Cakmak et al. identify tertiary lymphoid structures (TLSs) in a subset of gliomas that show signs of functional adaptive immune activation and are associated with longe…
TNF and type I IFNs are recognized as important drivers of skin inflammation. Priem et al. show that LC3-independent autophagy represses the ability of TNFR1 to directly trigger cGAS/STING-dependent type I IFN production and ZBP1 cytotoxicity, which pr…
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…
The Pfs230:Pfs48/45 complex is the target of leading anti-malaria transmission-blocking vaccine candidates, yet its molecular assembly is poorly understood. Bekkering, Yoo, Hailemariam, et al. determined the cryo-electron microscopy structure of the en…
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…
Benamar et al. demonstrate that Notch3+ Treg cells are increased in multiple sclerosis and in EAE. They are induced in the gut by microbiota and translocate to the CNS to degenerate into pathogenic Th17 cells. They also outcompete a protective NPY1R+-r…
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…
Type-1 regulatory T cells (Tr1) promote immune tolerance during chronic infection, autoimmunity, and transplantation, but the role of Eomes in Tr1 differentiation and function after cell therapy is unclear. Zhang et al. find that Eomes controls the acq…
S. aureus skin colonization is associated with food allergy in atopic dermatitis, but the mechanism of this association is unknown. Das et al. reveal that cutaneous exposure to S. aureus causes a basophil influx into skin-draining lymph nodes that driv…
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…
The term “extrafollicular” is now being used expansively to describe a variety of B cell processes beyond the original use of the term, potentially obscuring important distinct immunological processes. We discuss current uses of the term extrafollicula…
While microglial activation is a hallmark in neurodegeneration, the specific role of microglia in disease-related cortical excitability remains unknown. Xie et al. reveal that rod-shaped microglia form in response to early cortical hyperactivity in a m…
Triple-negative breast cancer (TNBC) is characterized by high risks of relapse or metastatic disease. Mattavelli et al. identify a chemokine axis that recruits immunosuppressive monocytes to tumor-draining lymph nodes. By co-targeting this recruitment,…
Integrin CD103 mediates memory T cell tissue residency by binding E-cadherin-expressing epithelial cells, but why CD103 is also expressed on circulating naive CD8+ T cells has been unclear. Li et al. report that CD103 facilitates the interaction of nai…
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…
