Circumventricular organs (CVOs) are small brain regions lacking a blood-brain barrier, giving neurons direct access to blood-borne signals, yet how these microenvironments shape the origin and phenotype of local macrophages remains unclear. Using multi-omics, we characterized the immune landscape of two CVOs, the area postrema (AP) and median eminence (ME), revealing brain-border-like environments with a unique macrophage compartment. CVO microglia showed a distinct, heterogeneous phenotype, including a CLEC7Ahigh myelin-associated subset in the ME, shaped by ageing and metabolism. CVO microglia were ontogenically diverse: fetal monocytes entered the CVOs perinatally and generated long-lived monocyte-derived microglia that fully adopted a yolk-sac-derived microglia identity. After depletion, CVO microglia were repopulated by local Sall1high cells but also by monocytes in the AP. Similarly, perivascular CVO border-associated macrophages displayed a distinct phenotype and origin. Our findings establish CVOs as specialized immune niches that shape local macrophages, reflecting the immune and metabolic demands of these environments.

Circumsporozoite protein (CSP) is the most abundant Plasmodium sporozoite surface antigen. It is the major component of licensed Plasmodium falciparum vaccines and, hence, is the logical lead candidate for Plasmodium vivax (P. vivax) vaccines. However, our limited knowledge of protective B cell epitopes on P. vivax CSP remains a major roadblock. Here we identified two Plasmodium vivax CSP (PvCSP) B cell epitopes, PvCSP-A and PvCSP-B/NAGG, by screening inhibitory plasma from P. vivax-infected individuals. The epitopes were located in the N- and C-terminal regions of PvCSP, respectively, and were distinct from the canonical central repeat region epitope. We isolated a monoclonal antibody, GRAM-4, that recognized the PvCSP-B/NAGG epitope and mediated potent inhibition of traversal, hepatocyte invasion, and liver-stage development in vitro, confirming PvCSP-B/NAGG as a genuine neutralization target. Structural resolution of the GRAM-4:PvCSP-B/NAGG interaction at 2.65 Å revealed the molecular basis of epitope recognition, providing a blueprint for PvCSP vaccine development.

Immunoglobulin E (IgE) drives allergy, yet how memory B cells (MBCs) reactivate to produce IgE, and how tissue localization shapes recall responses, remains unclear. Using mouse models of airborne exposure to house dust mites and Alternaria, we found that allergen sensitization generated lymph node (LN)- and lung-resident MBCs. Upon allergen re-exposure, MBCs follow two differentiation trajectories: a germinal center (GC)-dependent pathway, generating IgG1[+] and IgE[+] plasma cells (PCs) and occurring predominantly in LNs, and a GC-independent pathway, generating mainly IgG1[+] PCs and present in both organs. GC re-entry granted MBCs access to an interleukin (IL)-4-rich microniche formed by T follicular helper (Tfh) cells, which was essential for IgE production. Disrupting GC re-entry, IL-4 signaling, or Tfh cell-derived IL-4 during recall markedly reduced allergen-specific IgE. These findings reveal a spatially and cytokine-restricted mechanism that confines IgE memory to lymphoid organs, positioning GC IL-4 microniches as anatomical safeguards against IgE production at barrier sites frequently exposed to environmental antigens.

Environmental allergens are enriched in protease activity, which activates cutaneous sensory neurons, triggering itch and substance P release to promote migration of T helper (Th)2 cell-skewing CD301b[+] dendritic cells and initiate allergic immunity. However, allergens are typically encountered through repeated subthreshold exposures, and how these cumulatively induce sensitization is unknown. We identified a sensory neuron-intrinsic mechanism of neuroimmune memory. Protease allergen exposure induced sustained mechanistic target of rapamycin complex 1 (mTORC1) kinase signaling and transcriptional activator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-associated mitochondrial remodeling in sensory neurons, establishing a metabolically primed state with enhanced neuronal responsiveness. Upon allergen re-exposure, this state drove enhanced itch, CD301b[+] dendritic cell migration, and Th2 cell differentiation. Disrupting neuronal mTORC1 signaling or mitochondrial stability abrogated this amplification while sparing primary responses. This mechanism generalized across distinct protease allergens, revealing mTORC1-driven metabolic reprogramming in sensory neurons as a form of innate neuroimmune memory underlying allergen cross-sensitization and polysensitization.

TP53 mutations occur early in malignant transformation as truncal events in tumor evolution and are therefore generally present in all descendant tumor cells, creating an immunological vulnerability. Here, we examined the immunogenicity and antigenicity of p53 neoantigens emerging from these truncal mutations. Comprehensive immunopeptidomics revealed that hotspot mutations in human tumors preferentially localize to p53 regions resistant to antigen processing, thereby avoiding display altogether. Moreover, for neoantigens presentable by HLA-A[∗]02:01 or HLA-B[∗]07:02 and structurally divergent from corresponding wild-type p53 peptide-HLA complexes, clinical tumors commonly lacked the relevant presenting HLA allele. Tumor cells further resisted T cell killing through increased activity of the aminopeptidase ERAP1, preventing display of high-affinity HLA-A[∗]02:01 complexes containing an immunogenic p53[I195F]-derived 11-mer, or by expressing low-affinity HLA-A[∗]02:01 complexes containing a p53[R175H]-derived 9-mer with poor antigenicity despite high-quality human TCRs. These findings define mechanisms by which tumors restrict targetable truncal neoantigen display and suggest immunopeptidome shift strategies to circumvent immune escape.

Accumulating evidence implicates sensory neurons in tumor progression, but signals linking nociceptive activity to impaired antitumor immunity remain unclear. In a recent issue of Cell, Ho et al. show that nociceptor activation impedes TLS assembly through CGRP, and cigarette smoke engages this neuroimmune axis, promoting tumor growth independently of mutagenic effects.

Candida albicans induces Th17 cells, but their origins remain unresolved. In this issue of Immunity, Martini et al. show that the mouth is a reservoir for fungal Th17 cells that adopt pathogenic signatures in the gut during Crohn's disease.

Antigenic and environmental stimuli sensed by innate and adaptive immune cells trigger cognate functions that allow the coordination of the appropriate immune response. In this issue of Immunity, Tzerpos et al. and Jay et al. demonstrate that chromatin architecture dynamics integrate sensory inputs with functional outputs to regulate and direct immune cell responses.

The unprecedented recent advancement in the field of interoception (sensing self) has introduced neuromodulation as a realistic treatment approach. Shibuya et al. identified an ear-to-lung reflex in which activation of auricular-innervating TRPV1[+] vagal sensory neurons functions through neuropeptide CGRPβ to suppress allergic airway inflammation, providing an elegant example of exteroceptive control of interoception and a mechanism for transcutaneous neuromodulation.

Asthma is a heterogeneous disease characterized by airway hyperreactivity (AHR) and chronic cough, exacerbated by respiratory viruses or allergen exposure. Yet, the immune pathway-mediated serotonergic circuits underlying these responses remain poorly defined. Here, we identified a serotonergic neuroimmune axis in which pulmonary group 2 innate lymphoid cells (ILC2s) expressed tryptophan hydroxylase-1 (Tph1) and released serotonin via CCAAT/enhancer-binding protein beta (C/EBPβ)-dependent transcription following interleukin (IL)-33 stimulation. Tph1 deficiency in ILC2s and adoptive transfer experiments demonstrated that ILC2-derived serotonin amplified type 2 cytokine production via 5-hydroxytryptamine (5-HT)2A-NF-κB activation, resulting in exacerbated AHR in respiratory syncytial virus-driven asthmatic models. Using engineered viral tools, we showed that ILC2-derived serotonin sensitized vagal sensory neurons through 5-HT3A to promote cough hypersensitivity. Clinically, asthma patients exhibited elevated TPH1 and plasma serotonin levels, both of which correlated with type 2 cytokines. Together, these findings reveal that an ILC2-driven serotonergic circuit contributes to asthma pathophysiology and highlight serotonergic signaling as a therapeutic target.

Antibody imprinting is well recognized, yet its long-term dynamics and epitope specificity remain poorly understood. Here, we studied individuals sequentially infected with SARS-CoV-1 (SARS-1) and SARS-CoV-2 (SARS-2) over two decades and found durable imprinting of antibody responses following SARS-2 BF.7 breakthrough infection. Approximately 60% of isolated monoclonal antibodies were SARS-1 imprinted and targeted conserved receptor-binding domain regions, whereas 37% overcame imprinting to recognize the SARS-2 receptor-binding motif overlapping the ACE2-binding site. Notably, some SARS-1-only antibodies retained germline-like features and neutralizing activity 20 years after infection. One exceptionally imprinted broadly neutralizing antibody, THZ937, protected hamsters against contact and airborne transmission of Omicron EG.5.1, demonstrating the functional relevance of durable imprinted antibodies. Together, these findings define the remarkable longevity and molecular basis of antibody imprinting and provide insights for pan-sarbecovirus vaccine design.

Autoantibodies (autoAbs) are linked to mortality and Long COVID, yet their cellular origins remain unclear. We analyzed the INCOV cohort and identified 12 age- and sex-matched participants with varying autoAb abundance and integrated single-cell RNA-seq and ATAC-seq data from B cells, plasma proteomics, proteome-wide autoAb profiling, clinical data, and in vitro assays. AutoAb abundance inversely correlated with neutralizing IgG and declined as infection resolved, paralleling the contraction of atypical memory B cells (AtMs). In vitro, AtMs preferentially differentiated into autoAb-producing antibody-secreting cells upon TLR7/8 stimulation. CD11c[+] AtMs (double-negative 2, DN2s) in autoAb-high individuals exhibited increased TLR7 signaling, oxidative stress, and isotype switching, regulated by transcription factors T-bet and XBP1. Integrated genetic and genomic analyses showed that DN2s had the strongest enrichment for autoimmune trait heritability and inferred regulatory effects of autoimmune risk variants among B cell subsets. These findings identify DN2s as key precursors of autoAb-producing cells during SARS-CoV-2 infection.

Deeper understanding of the temporal immune response architecture in sepsis may enable effective therapeutic interventions. Here, we investigated longitudinal immune response programs in critically ill patients with sepsis, as compared with elective cardiac surgery patients. Although transcriptomic profiles obtained at four clinical time points between admission and recovery or death showed substantial overlap, pseudotime analysis revealed a trajectory comprising three sepsis temporal immune states (STImS1-3). Weighted gene co-expression network analysis and immunophenotypic and cytokine profiles identified distinct programs associated with each STImS, and corresponding hub genes mapped to putative immunomodulatory targets, including interleukin 6 blockade, iron chelation, and anthracyclines. STImS1 was characterized by the strongest innate immune responses, elevated resistance programs, variable disease tolerance programs, and enrichment of low-resilience features, including mortality-associated signatures. In contrast, STImS3 was enriched for adaptive immune responses. Thus, clinical time and immune response trajectory are partially decoupled in sepsis, illustrating the need to align therapeutic intervention with the temporal immune state in sepsis.