Altered astrocyte-microglia interactions have been implicated in the pathogenesis of Alzheimer’s disease, but the underpinning mechanisms remain unclear. Zhang and colleagues show that astrocytic PAD2-mediated citrullination of vimentin activates micro…
The presence of tertiary lymphoid structures (TLSs) associates with improved anti-tumor immunity, and as such, understanding why some tumors develop TLSs is of prime interest. In the current issue of Cancer Cell, Kirschstein et al. demonstrate that TGF…
by Mingyang Yin, Tao Liang, Yumeng Zhang, Guangchuan Wang, Wei Yang, Chenqi Xu
Cholesterol metabolism is an essential component of all immune cells. Xu and colleagues review the immunological functions of cholesterol metabolites and proteins and discuss how distinct cholesterol metabolic programs fulfil the metabolic and signalin…
Fibroblasts are highly attuned for immune crosstalk within lymphoid tissues. In this issue of Immunity, Alouche et al. provide insight into how fibroblast immunoregulatory phenotypes are acquired and maintained, revealing that Ccl19hi fibroblastic reti…
Systemic lupus erythematosus is characterized by autoantibodies against nuclear antigens. In this issue of Immunity, Al Souz et al. report that kidney damage in lupus nephritis is sustained by stem-like CD8+ T cells that migrate from lymphoid tissues a…
Preservation of host fitness is a common feature of longevity and immunity to infection. In this issue of Immunity, Triana-Martinez et al. reveal that p16High senescence-associated immune cells promote disease tolerance and healthy aging. Mechanistical…
Research that is done but never shared does not make a sound. Science communication can take many forms and has many audiences, from research colleagues to the general public. Here, investigators discuss the importance of engaging in the dissemination …
Patients with psoriasis show a durable clinical response to the anti-IL-23 biologic, risankizumab, even after treatment cessation. Here, Jiang et al. generate a longitudinal single-cell and spatial transcriptomics atlas of patients pre- and post-treatm…
Lobel, Fonseca-Pereira, et al. demonstrate that dietary sulfur amino acids (Saa) enhance anti-tumor immunity in colon cancer. A high-Saa diet expands the bacterium Mucispirillum schaedleri, which activates a natural killer T cell-dendritic cell axis to…
B cell infiltration in high-grade serous ovarian cancer associates with favorable prognosis. Nathan et al. show that tumor-draining lymph nodes in patients lack active germinal center responses and instead harbor quiescent tumor-reactive memory B cells…
Diet impacts gut microbes and, subsequently, host immunity, but our understanding of the mechanisms driving this axis remains incomplete. Hattori-Muroi, Maruta, Takahashi, et al. show that dietary soy promotes colonization of commensals that cooperativ…
The role of non-infiltrating aged CD8+ T cells in brain function remains unclear. Sucharov et al. reveal that aged circulating cytotoxic T cells are drivers of age-related cognitive decline. Removal of aged T cells, or their secreted factor granzyme K,…
Under homeostatic conditions, murine dendritic cells (DCs) undergo a tolerogenic activation termed homeostatic maturation, preventing autoimmunity by inducing tolerance to innocuous antigens; whether this process occurs in humans is unknown. In this is…
by Dominic S. Albao, Shashank D. Nagaraja, Matthew E. Pipkin
CD8+ T cells responding to chronic infections are functionally and spatially heterogeneous. In this issue of Immunity, Shen et al. and Geng et al. demonstrate that the transcription factors KLF2 and KLF3 have integrated but opposing roles in regulating…
Severe pediatric autoimmune diseases (AD) have limited therapeutic options. In a recent issue of Nature Medicine, Becilli et al. report a case series where CD19 CAR T cell treatment of pediatric AD patients induced rapid and durable remissions with man…
The gut microbiome contributes to age-related cognitive decline, but signaling mechanisms remain unclear. In a recent issue of Nature, Cox et al. show that P. goldsteinii-derived fatty acids activate myeloid cells, thus inducing inflammation that disru…
Defining correlates of HIV rebound upon antiretroviral therapy (ART) interruption can advance HIV cure research. In this issue of Immunity, Ma et al. analyze immunophenotypes and transcriptomes from multiple clinical trials, linking T and NK cell subse…
Tumors present metabolic challenges for T cells. In this issue of Immunity, Scaglione et al. show that CD8+ T cells adapt to nutrient stress through biosynthetic plasticity, coupling translational reprioritization to metabolic reprogramming, preserving…
The mechanisms linking defective protein prenylation to systemic inflammation in mevalonate kinase deficiency remain unclear. Munoz et al. reveal that mice and humans with MKD have defective NK cells, with impaired granule trafficking, reduced cytotoxi…
CD8+ T cells must retain functional resilience as they traverse diverse environments. Scaglione et al. reveal how the integrated stress response enables CD8+ T cells to engage alternate biosynthetic modes under environmental stress that prevent dysfunc…
Ulezko Antonova et al. examine plasmacytoid dendritic cells (pDCs) in lymphoid tissues from infancy to adulthood and identify a cycling population of pDCs in fetal and infant lymphoid organs that is found only in the bone marrow in adults. pDCs in sepa…
Geng et al. identify KLF2 as a central regulator of CX3CR1+ effector-like exhausted CD8+ T cells during chronic infection. KLF2 is uniquely expressed and both necessary and sufficient for this state. Disrupting the KLF2-dependent program enhances viral…
Tumor-associated macrophages (TAMs) can limit anti-tumor immunity. Sun et al. find that SPP1+ TAMs are enriched in tumors across cancer types and associated with resistance to immune checkpoint blockade. Mechanistically, SPP1 interacts with TRIM21 to l…
Advancements in human genetics have catalyzed rapid discovery in immunology. Graham and Xavier review how functional genomics and chemical biology have joined forces to uncover mechanisms of mucosal immunity and the pathophysiology of inflammatory bowe…
TREX1, but not other DEDDh exonucleases, restrains cGAS-STING activation by cytosolic DNA. Zhu et al. examine the basis for this specificity and define a modular double-stranded DNA (dsDNA)-recognition architecture within TREX1 comprising R128, a subst…
Specialized fibroblastic reticular cell (FRC) subsets in lymph nodes orchestrate the compartmentalization that guides immune cell migration, interaction, and function. Alouche et al. examine the signals governing FRC differentiation and identify a Notc…
MAIT cells acquire effector-memory and tissue-residency programs in the thymus. Paiva et al. demonstrate that MAIT cells can be selected by epithelial cells and egress the thymus at several developmental stages with subset-specific tissue tropisms and …
Loss of B cell tolerance, autoantibody production, and immune complex deposition are hallmarks of systemic lupus erythematosus. Al Souz et al. find that kidney-infiltrating CD8+ T cells differentiate from stem-like precursors in renal lymph nodes and c…
Intestinal microbiota can have both local and systemic effects on immunity and inflammation. Here, Yu et al. find that intestinal dysbiosis exacerbates atopic dermatitis pathology. Shifts in microbial abundances lead to elevated systemic levels of micr…
Using scRNA-seq of skin-innervating neurons, Voisin et al. show that skin-projecting nociceptor subpopulations differentially integrate the inflammatory response during allergic contact dermatitis. Although peptidergic TRPV1+ neurons control neutrophil…
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…
In Alzheimer’s disease (AD), glial crosstalk surrounding amyloid-β (Aβ) plaques establishes a self-reinforcing inflammatory circuit; however, its underlying mechanisms are incompletely understood. Zhang et al. find that astrocytic PAD2 citrullinates vi…
Vendramin et al. identify nonsense-mediated mRNA decay (NMD) as a central constraint on tumor antigenicity. Inhibiting the NMD kinase SMG1 stabilizes aberrant NMD-targeted transcripts and reveals a previously inaccessible class of non-canonical, non-mu…
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…
The prostate is an important exocrine gland and barrier tissue of the male reproductive system, yet prostate Trm cells remain uncharted. Takehara et al. utilize functional genetics and single-cell and spatial transcriptomics to identify the molecular r…
Different clinical courses of HCV infection shape CD4+ T cell immunity. Reinscheid et al. show that a stem-like subset of CD4+ T cells arising during chronic infection is maintained after successful antiviral therapy and establishes long-term memory th…
Antibody responses following primary SARS-CoV-2 infection or mRNA vaccination are well described, but B cell phenotypes, receptor genetics, and antigen factors that determine initial viral variant binding breadth are less established. Wirz et al. find …
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…
How Foxp3 establishes the epigenetic and transcriptional identity of regulatory T (Treg) cells remains unclear. Murakami et al. demonstrate that Foxp3 cooperates with the AP-1 transcription factor BATF to directly promote chromatin accessibility and ge…
Perinatally acquired persistent viral infections are thought to result in T cell tolerance. Martin et al. show that neonatally LCMV-infected mice mount virus-specific Tfh cell responses that are transcriptionally normal but clonally restricted. These r…
Aging is accompanied by significant changes to the immune system. Allen et al. demonstrate that age-related NF-κB activation in fibroblasts remodels the lung resident immune system and promotes the emergence of pro-inflammatory Gzmk+ T cells. This work…
Stanbery et al. show that ILC2s are largely dispensable, but tuft cells remain essential for helminth clearance during secondary infection. Tuft cells are not required for Th2 priming. Instead, tuft cell effectors directly activate memory Th2 cells in …
During chronic viral infection, CD8+ T cell exhaustion is closely linked to altered migration and tissue residency. Shen et al. identify a reciprocal KLF2-KLF3 transcriptional circuit that controls cellular localization and show that enforcing T cell m…
Cellular senescence is traditionally linked to aging and tissue dysfunction, yet whether beneficial p16High cells can protect against acute lethal stress remains unknown. Triana-Martinez et al. demonstrate that the BNT162b2 mRNA vaccine exerts strong p…
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…
To identify factors that can mediate post-ART HIV control, Ma et al. performed “omics” on PBMCs from PWH from 4 analytical treatment interruption cohorts. NK and T cell features were identified, and the top two genes in CD4+ T cells predicting delayed …
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…
While dendritic cells (DCs) are central to adaptive immunity against pathogens, their specific role in maintaining peripheral self-tolerance in humans remains poorly defined. Lu et al. uncover a distinct homeostatic maturation state in human cDC2s (ter…
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,…
