by Iker Ramírez Lapeña, Stephanie C. Ganal-Vonarburg
While pregnancy suppresses systemic immunity to tolerate the fetus, adaptations of the gut remain unclear. In a recent issue of Nature, Huang et al. show that reproduction increases intestinal eosinophils, shifting intestinal stem cell fate toward gobl…
Metabolic alterations and neutrophils define the pre-metastatic niche, but the mechanisms connecting them remain incompletely understood. In this issue of Immunity, Qian et al. show that endothelial-derived palmitate induces neutrophils to release lipo…
Extracellular ATP (eATP) is an immunogenic danger signal. In this issue of Immunity, Hu et al. report that in the tumor microenvironment, eATP signals through the receptor P2RY2 on cancer cells, triggering the COX-PGE2 pathway and thereby immune suppre…
Similar to CD8+ T cells, stem-like CD4+ T cells sustain responses to tumors, chronic infections, and inflammation. In this issue of Immunity, Wen et al. and Agesta et al. reveal EOMES as a critical regulator of stem-like CD4+ T cell maintenance and dif…
Aging and chronic inflammation alter hematopoiesis, impacting the hematopoietic progenitor populations in the bone marrow. In this issue of Immunity, Yao et al. show that the canonical type 2 cytokine interleukin 4 reverses age-related hematopoietic an…
In April of this year, our community lost one of its most brilliant and beloved members, Philippe Bousso. With his unique scientific vision, love of technical innovation, and his generous and kind spirit, Philippe touched many of our lives and gave us …
Recurrence is a major clinical challenge in hepatocellular carcinoma (HCC). Gu et al. examine human HCC samples to identify drivers of disease recurrence and find that inhibiting the cholesterol esterification enzyme SOAT1 impairs tumor redox resilienc…
West Nile virus and other neurotrophic arboviruses can cause life-threatening encephalitis. Lewy et al. identify a cross-organ immune circuit where viral pattern sensing in the skin potently counteracts viral encephalitis. Mechanistically, the establis…
Extracellular ATP (eATP) is associated with immune suppression in the tumor microenvironment (TME) via its metabolite adenosine. Hu et al. find that immunotherapy increases eATP within the TME and drives immune suppression through direct binding of the…
Aerobic glycolysis, a hallmark of cancer, preferentially converts pyruvate into lactate. Guo et al. demonstrate that tumor aerobic glycolysis drives lactate production through PKM2-mediated phosphorylation and activation of LDHA. Lactate directly binds…
Understanding FcγR engagement and signaling is central to improving monoclonal antibody therapeutics. Using structural, biophysical, and cellular immunology approaches, Fisher et al. demonstrate how disparate off rates drive the agonism and antagonism …
The transcription factor Eomes orchestrates the differentiation and maintenance of an exhausted-like Th cell lineage that is transcriptionally and functionally distinct from conventional effector and memory Th subsets. This lineage is amplified by 4-1B…
CD4+ T helper cells are essential for adaptive immunity; however, factors governing their maintenance and function during chronic antigen exposure remain unclear. Wen et al. identify a precursor T cell population, dependent on TOX, EOMES, and MYB, that…
No specific prophylaxis or treatment exists for West Nile virus (WNV) or related orthoflavivirus infections. Cervantes Rincón et al. characterize human antibody responses to WNV and identify protective epitopes on the virus envelope protein. A potent m…
Neutrophils have the capacity to both support and block tumor growth depending on their polarization state. Here, Pei et al. find that IFN-γ produced during immunotherapy induces PD-L1 expression by neutrophils with an aged phenotype that drives therap…
Borden et al. examine primary, treatment-naive squamous cell carcinoma (SCC) tumors to determine the impact of immunoediting. Comparison of SCC tumors from immunocompetent and immunosuppressed patients demonstrates immune-mediated sculpting of the tumo…
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 …
Chronic inflammation and aging skew hematopoiesis toward myelopoiesis. Starting with a screen to identify signals capable of restoring lymphoid lineage commitment in HSPCs, Yao et al. find that exogenous interleukin 4 can drive lymphoid differentiation…
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…
Exercise is increasingly linked to improved immune function across diseases, yet the underlying mechanisms remain incompletely understood. Meisel et al. synthesize how acute exercise and sustained training reshape immune-cell trafficking and function t…
T follicular helper 13 (Tfh13) cells are required for anaphylactic IgE responses, yet how these cells arise is unclear. Lee et al. show that allergen sensitization drives CCR8-dependent trafficking of ILC2s to lymph nodes, where they provide early IL-4…
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,…
T follicular helper (Tfh) cells are essential for humoral immunity but can promote autoimmunity when dysregulated. Wang et al. identify a mevalonate pathway-dependent program in which GGPP supports Tfh cell differentiation by sustaining surface protein…
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…
Therapeutic monoclonal antibodies are central to cancer treatment but often show incomplete efficacy. Cheng et al. demonstrate that transient host-cell glycoengineering to reduce N-glycan trimming strengthens IgG-FcγRIIIa bond resilience under vascular…
Pre-metastatic niche formation is a pivotal driver of breast cancer lung metastasis; however, the mechanisms underlying changes in vascular endothelial permeability remain unclear. Qian et al. demonstrate that triple-negative breast cancer-induced palm…
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…
