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…
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…
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…
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…
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…
Tissue-resident memory T cells (Trms) are key to mucosal immunity. Wei et al. show that BACH2 restrains Trm effector function to reduce excessive inflammation and promote long-term tissue residence. HIV persists in gut Trm Th17 cells through a BACH2-sh…
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-…
