Memory T (TMEM) cells are designated as either circulating (Tcircm) or tissue-resident (Trm) populations. In this review, Jameson and Hamilton examine the attributes of Tcircm cells and discuss the features and functional heterogeneity of distinct Tcir…
Tissue-resident memory T (TRM) cells provide local, organ-specific immunity and are shaped by their position within these tissues. This review outlines how priming-associated programming, niche-level microenvironments, and local antigen exposure define…
Although B cell development is a well-studied field, we are only beginning to appreciate the diversity and complexity of plasma cell formation and function. In this review, Fields and Bhattacharya discuss factors impacting plasma cell heterogeneity and…
Long-lived plasma cells maintain antibody titers that sustain humoral immunity, yet the physiological cues regulating their persistence remain incompletely understood. In this issue of Immunity, Zhu et al. reveal that fasting-induced β-hydroxybutyrate …
Regulated cell death is critical for both homeostasis and the response to infection. In this perspective, Tait and Oberst discuss how sub-lethal activation of canonical cell death pathways has lasting impacts on cells and tissues. These near-death cell…
Designing a universal influenza vaccine must address not only viral antigenic drift but also genetic variability in human antibody responses. In this issue of Immunity, two studies from the Karlsson-Hedestam lab (Corcoran et al. and Fischer et al.) int…
The immune system is a key contributor to organismal aging. Here, Ping et al. leverage single-cell multi-omics to construct a human immune aging clock, which pinpoints T cells as an aging nexus. RUNX1 orchestrates a transcriptional network that restrai…
Inducing broadly neutralizing antibodies (bnAbs) remains a challenge in HIV vaccine development. Mishra et al. show that an engineered germline-targeting HIV trimer, Q23-APEX-GT2, primes rare V2-apex bnAb precursors in humanized mice and outbred macaqu…
The generation of immune memory is at the crux of vaccine efficacy. Here, Crotty reviews the layers of adaptive immunity—T cell, B cells, and antibodies—and their integration to generate a holistic view of vaccine response. Common misconceptions and qu…
Innate immune cell death is critical for host defense but drives inflammatory disease when dysregulated. In this issue of Immunity, Huang et al. report that the complement protein C1q activates macrophage mitochondrial SARM1 to deplete NAD+ and produce…
A lethal feature of glioblastoma is its ability to spread within the brain. In this issue of Immunity, Nebeling et al. use longitudinal three-photon imaging in an immunocompetent glioblastoma model to show that microglial responses at the far infiltrat…
RORγt is a key transcriptional regulator across diverse immune subsets. In this issue of Immunity, Fukui et al. show how Runx controls RORγt expression during early development and link progenitor specification to the diversification of RORγt+ innate i…
by Georg Gasteiger, Thomas Ossner, Christin Friedrich
Immune experience can durably shape innate lymphocytes and their environments. Gasteiger and colleagues discuss how training, memory-like features, and dynamic niche interactions reprogram NK cells and ILCs to adapt their functions and tissue specializ…
by Sarah J. Sun, Raúl Aguirre-Gamboa, Luis B. Barreiro
In this review, Barreiro and colleagues synthesize molecular and cellular mechanisms of trained immunity across monocytes, tissue-resident macrophages, and HSPCs. They propose a unifying framework linking transcription factor activity, metabolic remode…
Regulatory T (Treg) cells are phenotypically stable in inflammatory settings. Maltez et al. report that αCD40 immunotherapy induced conversion of Treg cells into FoxP3−Tbet+IFN-γ+ “ExTreg” cells within the tumor microenvironment. ExTreg cells exhibited…
by Sarah Adamo, Joel G. Rurik, Claire E. Gustafson, Marcus Buggert
Aging profoundly alters memory T cell immunity, reshaping diversity, differentiation, and function. Adamo et al. review how intrinsic aging programs, antigenic experience, and tissue context shape T cell responses and discuss emerging strategies to rec…
Infiltration of glioblastoma (GB) cells into the brain parenchyma and colonization of distant regions are associated with disease recurrence and therapy resistance. Using 3-photon intravital microscopy in an autochthonous GB model, Nebeling et al. iden…
Although long-term dietary effects on the immune system are well established, how short-term high-fat diet (HFD) alters intestinal immunity is less understood. Here, Torrico et al. show that within hours of initiating HFD, microbiota-driven inflammatio…
Variation in antibody genetics, as illustrated in the accompanying paper by Corcoran et al., can present a challenge to the development of population-wide protective vaccines. Fischer, Corcoran, et al. investigate influenza-specific antibodies to obtai…
Transcription factor RORγt is a central regulator of type 3 immunity, essential for host defense and tissue homeostasis. Fukui et al. identify a hierarchical CNS11-CNS9 enhancer cascade that governs RORγt expression across innate lymphocytes and antige…
The genes that encode our antibodies display extensive variation between individuals. Corcoran et al. developed a high-throughput sequence-based method for identifying variations in antibody genes (ImmuneDiscover). This enabled the sequencing of 2,486 …
Microplastics are detectable in diverse human tissues, yet their biological impact remains unclear. In this issue of Immunity, Codo et al. dissect the mechanisms involved and find that polystyrene microplastics inhibit tissue-resident phagocyte clearan…
Sick animals often show reduced social engagement, a form of adaptive behavioral distancing thought to limit pathogen transmission beyond the infected individual. In a recent issue of Cell, Yang et al. identified a defined molecular and anatomical path…
The human antibody repertoire is broadly reactive with carbohydrate antigens represented in the host/self as well as the commensal microbiota. New et al. find that B cells reactive with the glycan constituent N-acetyl-glucosamine arise early in life an…
Vaccines targeting bacterial glycans can elicit inconsistent and/or poor protection in the young. Fryer, Pitt, et al. show that mucosal S. pyogenes infection triggers a glycan-specific B cell response that evolves with age and includes antibody class s…
Pre-existing antibodies restrict naive B cell entry into germinal centers, but how antibody feedback shapes ongoing reactions is unclear. In this issue of Immunity, Barbulescu et al. and Yan et al. show that antigen binding by locally produced high-aff…
Natural killer (NK) cells hold promise for cancer immunotherapy but show limited persistence in solid tumors. In this issue of Immunity, Ji et al. reveal that nutrient stress induces FLI1-mediated repression of pro-survival unfolded protein response pr…
Immune responses are energetically costly and must adapt to systemic nutrient availability. How immunity is reorganized to preserve host glucose during caloric restriction remains unclear. In this issue of Immunity, Menezes-Silva et al. show that dieta…
Intraocular pressure (IOP) is dysregulated in glaucoma, a leading cause of blindness. Immune contributions to IOP maintenance are poorly understood. Liu et al. reveal that long-lived resident tissue macrophages have a specialized role in IOP homeostasi…
Rheumatoid joints contain macrophages with reparative potential, yet inflammation persists. Huang et al. demonstrate that these homeostatic macrophages lose their protective role by undergoing PANoptotic death. Mechanistically, C1q activates the mitoch…
Tertiary lymphoid structures are critical components of tissue immunity, necessitating better understanding of their organization and immune functions. De Lima et al. investigate the spatial and temporal distribution of lung HIF-1α-active CD4⁺ T cells….
Resident macrophage maturation and tissue-specific identity depend on transcriptional programming, yet how conserved regulators universally drive these programs remains unresolved across tissues. Vanneste et al. identify MafB as a key transcriptional r…
by Xiaoying Chen, David M. Holtzman, Marco Colonna
Alzheimer’s disease (AD) is driven by dynamic interactions between innate and adaptive immunity. Colonna, Chen, and Holtzman review recent advances in the genetic and mechanistic understanding of how microglia and T cells shape AD progression, and disc…
Understanding immunity against Plasmodium vivax, a leading cause of malaria, will accelerate development of vaccines, which are currently lagging. Opi et al. identify important mechanisms and target antigens of protective P. vivax immunity in children,…
Using a dual-recombinase fate-mapping system to trace late-entry invader B cells in germinal centers, Zhou et al. show that across vaccination and influenza infection, invaders preferentially generate memory B cells, whose antibodies target subdominant…
Broadly neutralizing antibodies are promising therapeutics for ending the HIV pandemic; however, their clinical efficacy is undermined by viral escape. Galvez, Nitido, et al. could drive the therapeutic outcomes of vectored immunotherapy in humanized m…
Neuroimmune interactions shape host responses to infection, but the molecular role of sensory neurons during viral infection remains unclear. Roger et al. show that HSV-1-activated sensory neurons produce substance P and TAFA4, which act in a tissue-sp…
γδIELs are essential for intestinal homeostasis, but how their differentiation and cytotoxic function are regulated remains unclear. Xie et al. demonstrate two functionally distinct γδIEL subsets, CD160+TCF1+BCL6+ stem-like and GZMB+BLIMP1+ effector-li…
Antibodies generated by prior immune responses regulate B cell responses upon recall immunization. Barbulescu et al. examine whether antibodies produced by an ongoing immune response influence the outcomes of contemporaneous germinal centers (GCs) and …
Microplastics pose a substantial threat to human health, but their effect on phagocytosis is unknown. Codo et al. find that polystyrene microplastics accumulate in different types of tissue-resident phagocytes, disrupting homeostatic clearance of apopt…
Vaccine-induced long-lived plasma cells protect the host by secreting neutralizing antibodies, yet the mechanism regulating their lifespan remains unclear. Here, Zhu et al. reveal that fasting depletes long-lived plasma cells and thus impairs humoral i…
Emotional stress worsens atopic dermatitis and its overall burden, yet the underlying mechanisms remain unclear. Xie et al. reveal that anxiety amplifies atopic dermatitis through sympathetic nervous system activation. Sympathetic release of norepineph…
Tumor-infiltrating NK cells are often dysfunctional. Ji et al. show that the solid tumor microenvironment metabolome drives proteostasis imbalance and dysfunction in tumor-infiltrating NK cells and demonstrate that deletion of Fli1, a transcriptional r…
The cytosolic LPS sensor caspase-4 controls antibacterial immunity by inducing pyroptosis and cytokine secretion. Began et al. show how remodeling of LPS membranes by interferon-induced GTPase GBP1 promotes the formation of positively curved membrane r…
Feedback from circulating antibodies can shape initiating immune responses. Yan et al. examine ongoing germinal center (GC) responses upon immunization with an mRNA-LNP-encoded membrane-bound immunogen displaying three conserved HIV-1 envelope epitopes…
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…
When food availability is reduced, it is unclear how the host adapts to support glucose-demanding immune processes while preventing hypoglycemia. Here, Menezes-Silva, Jeong, et al. demonstrate that glucocorticoids (GCs) maintain immune homeostasis, and…
Respiratory infection and cardiovascular disease risk are tightly intertwined clinically, but the mechanisms of this relationship are largely unknown. Here, Downey et al. reveal how influenza traffics to the heart from the lung largely within pro-DC3s,…
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…
