Journal of Experimental Medicine

We previously reported inherited RORgammaT deficiency in seven patients from three ancestries (Chilean, Palestinian, Saudi Arabian) with mycobacterial disease and chronic mucocutaneous candidiasis (CMC). We report here five additional patients from different ancestries (Afghan, Indian, Iranian, Japanese, Sri Lankan), each homozygous for a new loss-of-function RORC variant. All but one patient, the exception receiving early prophylaxis, developed mycobacterial disease due to a near-complete depletion of innate-like adaptive T cells, including MAIT and iNKT cells, low counts of adaptive TH1* and CD8+ T cells, and impaired Mycobacterium-induced IFN-gamma production by the remaining cells of these subsets, NK cells, conventional CD4+ T, Vdelta1, and Vdelta2 gamma-delta T cells. Most patients also displayed CMC due to their low counts of TH17 and TH1* cells. One patient died from disseminated Bacille Calmette-Guerin (BCG) vaccine infection, but, unexpectedly, all the other patients are still alive and clinically stable. RORgammaT is essential for protective immunity against mycobacteria and Candida in humans.

Ribosome biogenesis defects are increasingly recognized in hematologic disorders, yet their contribution to human combined immunodeficiency (CID) remains largely unexplored. Here, we identify compound heterozygous mutations in GTF3A, encoding transcription factor IIIA (TFIIIA), in a patient with CID presenting with profound T-cell lymphopenia, diminished thymic output, and humoral failure. The patient-derived TFIIIA variants, I267S and L364Yfs*37, disrupted 5S rRNA transcription, impaired RNA-binding capacity, and compromised protein stability. Patient T and B lymphocytes exhibited intrinsic proliferative and differentiation defects, as well as increased apoptotic susceptibility in T cells, recapitulating the clinical phenotype. To model TFIIIA dosage, we generated heterozygous and progressively depleted Jurkat cell clones via sequential CRISPR editing; complete TFIIIA loss was lethal, whereas graded reduction impaired proliferation in a dose-dependent manner, fully rescued by wild-type GTF3A reconstitution. Collectively, these findings establish deficiency of GTF3A resulting in combined immunodeficiency (DoGCID) within the spectrum of ribosomopathies, highlighting the exquisite sensitivity of lymphocyte fitness to disruptions in ribosome biogenesis.

Molecular characterization of human monogenic inborn errors of T cell immunity provides both biological insights and medical progress. We report rare biallelic deleterious variants in GTF3A, encoding transcription factor IIIA (TFIIIA), a zinc-finger protein required for transcription and chaperoning of 5S ribosomal RNA (rRNA). These variants were identified in ten patients from eight unrelated families and eight countries presenting with either T-B+NK+ severe combined immunodeficiency (SCID) or combined immune deficiency (CID), characterized by T cell lymphopenia and variable antibody deficiency. The GTF3A variants disrupt TFIIIA function through distinct mechanisms, including defective DNA binding, aberrant nuclear localization, and reduced protein stability compromising TFIIIA-mediated transcription and chaperoning of 5S rRNA. Using artificial thymic organoids derived from TFIIIA-deficient CD34+ progenitors, an early developmental arrest at the T cell commitment stage was documented in vitro. Zebrafish deficient for gtf3aa recapitulated the impaired thymocyte development in vivo. Together, these findings establish TFIIIA deficiency as a novel cause of (S)CID, expanding the genetic and mechanistic landscape of inborn errors of T cell immunity and uncovering an essential role for TFIIIA in human adaptive immunity.

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder that affects lymph nodes at multiple sites and can progress to life-threatening organ dysfunction. While curative therapies remain unavailable, largely due to a critical gap in understanding the diseases underlying etiology, the cytokine interleukin-6 (IL-6) is recognized as a major pathogenic driver, particularly in iMCD patients with plasmacytic lymphadenopathy. Here, we demonstrate the presence of Foxp3-expressing cells alongside plasma cells within germinal centers of lymph nodes from such iMCD patients. Based on this observation, we directed IL-6 overexpression specifically to Foxp3+ Treg cells and established a novel preclinical mouse model of iMCD. This targeted approach successfully recapitulated the key characteristics of iMCD in mice, including multifocal lymphadenopathy, splenomegaly, anemia, thrombocytopenia, marked plasmacytosis, and mortality in young adults. Advanced disease was characterized by renal pathology, including proteinuria and elevated creatinine levels. In this model, IL-6 directly promoted plasmacytosis, resulting in profound IgG1 hyperimmunoglobulinemia. Genetic ablation of soluble immunoglobulin production ameliorated iMCD symptoms, prevented renal dysfunction, and significantly extended survival. Our findings identify IL-6-driven IgG1 plasmacytosis as a critical pathogenic factor in iMCD, shedding light on the mechanisms underlying its development. Key pointsO_LITransgenic IL-6 expression in Foxp3+ cells models iMCD in mice and drives lethal IgG1 plasmacytosis C_LIO_LILoss of soluble immunoglobulins prevented renal impairment and prolonged survival in iMCD-like mice C_LI

Tuft cells initiate intestinal type 2 immunity, yet the mechanisms that restrain excessive tuft cell activation remain poorly understood. Here, we identify the receptor tyrosine phosphatase CD45 (Ptprc), previously considered a hematopoietic marker, as a regulator of intestinal tuft cell function. CD45 expression is restricted to a subset of tuft cells and is induced by helminth infection and IL-13. Epithelial-specific deletion of Ptprc activated a tuft cell inflammatory program, promoted an epithelial inflammatory state, and increased eosinophil accumulation at homeostasis. During Heligmosomoides polygyrus bakeri infection, CD45 deficiency enhanced ILC2 and Th2 responses and reduced parasite burden, demonstrating that epithelial CD45 limits type 2 immunity in vivo. Accordingly, in intestinal organoids, CD45 was dispensable for IL-13-driven tuft cell differentiation but restrained IL-13-responsive transcriptional programs. Mechanistically, CD45-deficient tuft cells exhibited altered protein abundance of STAT5 and IL17RB, implicated in tuft cell immune regulation. Together, these findings identify CD45 as a tuft cell-intrinsic regulatory checkpoint that restrains intestinal type 2 immunity through an IL-13-induced negative-feedback circuit.

Antinuclear antibodies (ANAs) are a hallmark of connective tissue diseases (CTDs) and serve as robust diagnostic biomarkers. Because their cognate antigens are intracellular, ANAs have long been considered non-pathogenic in CTDs. Here, using systemic sclerosis (SSc) associated anti-topoisomerase I antibodies (ATAs) as a model, we provide data challenging this view. We show that ANAs enter living cells, accumulate in nuclei, and engage their intracellular antigen. Nuclear ATAs inhibit topoisomerase I enzymatic activity, induces DNA damage, fibrosis, and, through the STING pathway, activates type I interferon production. We further identify neonatal Fc receptor (FcRn)-dependent intracellular trafficking as a key determinant of ANAs nuclear access and demonstrate that pharmacological FcRn blockade impairs ATAs functionality. These findings reveal a previously unrecognized intracellular effector function of ANAs and establish a mechanistic framework by which ANAs may directly contribute to tissue injury in CTDs.

Primary CD8+ T-cell responses decline with age, increasing susceptibility to novel infections. Virtual memory (VM) CD8+ T cells are memory-phenotype cells that respond rapidly to infection and undergo marked expansion with age. Although aged VM cells exhibit functional impairment, cellular senescence, and clonal expansion, the mechanisms responsible for these changes remain poorly understood. Here, we show that the VM-cell compartment in aged mice is derived predominantly from cells generated early in life and maintained through continuous self-renewal. Over time, resident VM cells acquire increased competitive fitness, resulting in progressive enrichment of the resident population and exclusion of newly generated VM cells. Consequently, unlike the naive CD8+ T-cell compartment, which is continuously replenished throughout life, the VM-cell compartment becomes dominated by long-lived resident cells. Depletion of resident VM cells resets the aged VM-cell compartment and permits expansion of newly generated VM cells. These findings identify lifelong self-renewal and competition as key mechanisms shaping VM-cell aging.

Type 2 conventional dendritic cells (cDC2) orchestrate T cell immunity, yet the signals that regulate their tissue-specific functions across development remain poorly defined. We demonstrate that splenic cDC2/DC3 subset heterogeneity is established perinatally and that splenic ESAMhi cDC2A undergo a transcriptional and functional transition around the time of weaning, which occurs independently of microbiota. Comparative transcriptomics identified neonatal-specific regulatory programs, including elevated expression of Plaur, encoding CD87/uPAR. CD87 sensitizes neonatal ESAMhi cDC2A to coagulation factor XII (FXII), thereby enhancing their capacity to promote Th17 differentiation. In human infants, CD87 expression was high on cDC2, its expression declined with age and in plasma of preterm infants CD87 positively correlated with Th17-associated cytokines. Together, we identify a conserved link between coagulation pathways and cDC2 developmental programming that may offer new opportunities to modulate Th17 responses in infancy. SummarySplenic cDC2 undergo a transcriptional and functional remodeling around weaning. Elevated CD87 expression on neonatal cDC2 enhances their FXII-driven Th17 potential. Conserved in human infants, elevated CD87 expression reveals a coagulation-linked pathway shaping early-life dendritic cell function and suggests targets to improve vaccination.

Memory B cells (MBCs) are a critical cellular reservoir for long-term humoral immunity. MBCs display heterogeneous isotypes and surface markers and can arise through both germinal center (GC)-dependent and GC-independent extrafollicular (EF) pathways. Both the mechanisms controlling EF MBC differentiation and the identities of the B cell populations from which EF MBCs derive remain poorly understood. To capture MBC diversity, we applied a broad selection strategy followed by transcriptional profiling, identifying a subset of MBCs characterized by minimal class switching, limited somatic hypermutation, and an innate-like gene signature. Using genetic models, we demonstrated that this subset arises independently of GC responses and derives from innate B1 cells. These innate-like MBCs differentiate into antigen-specific antibody-secreting cells and confer protection against lethal viral infection. Together, our findings define a previously unrecognized arm of MBC responses, demonstrating that innate B1 cells contribute a non-redundant antibody repertoire to protective immunological memory.

compromises hematopoietic stem cell (HSC) maintenance, contributing to an extrinsic HSC aging phenotype. Although niche-derived Notch signaling is essential for hematopoietic regeneration following myelosuppressive injury, the upstream epigenetic mechanisms that regulate this stress-responsive signaling remain poorly understood. Here, we identify the chromatin remodeler BRM (SMARCA2) as a critical regulator of the BM sinusoidal niche that preserves vascular integrity and hematopoietic regeneration. Using reciprocal BM transplantation, we demonstrate that a Brm-deficient microenvironment impairs HSC repopulating capacity and imposes an aging-like myeloid bias characterized by expansion of granulocyte-monocyte progenitors. Following 5-fluorouracil (5-FU)-induced myelosuppression, BrmKO mice exhibit defective sinusoidal regeneration accompanied by endothelial degeneration. Mechanistically, BRM deficiency attenuates endothelial Notch signaling by impairing stress-induced Notch2 expression in sinusoidal endothelial cells (SECs), while simultaneously reducing Jag2 ligand pool through persistent depletion of SECs and impaired stress-induced expansion of Jag2-producing LepR-positive stromal cells. These alterations attenuate endothelial Notch signaling, resulting in defective sinusoidal regeneration, loss of mesenchymal niche support, and progressive displacement of HSCs from the sinusoidal vasculature. Notably, Brm expression is physiologically reduced in aged wild-type SECs and LepR-positive stromal cells. Collectively, our findings identify BRM as a key epigenetic regulator of bone marrow niche integrity and suggest that age-associated BRM decline contributes to niche dysfunction and hematopoietic aging.

Ubiquitin-dependent regulation of NF-{kappa}B signaling is essential for B-cell homeostasis and fate decisions, yet the contribution of specific deubiquitinating enzymes remains incompletely defined. OTUB1, a lysine-48-specific deubiquitinase, has been broadly implicated in immune regulation, including control of NF-{kappa}B signaling and prevention of immune hyperactivation. Previous studies have demonstrated that B cell-specific deletion of OTUB1 leads to B cell hyperplasia, increased antibody production, and lupus-like autoimmunity, highlighting its importance in maintaining B cell tolerance and immune homeostasis. Using B cell-specific OTUB1-deficient mice, we show that loss of OTUB1 leads to a marked expansion of marginal zone (MZ) B cells and their precursor populations in the spleen, accompanied by an activated phenotype and enhanced proliferative responses, particularly upon CD40 stimulation. OTUB1 deficiency results in altered CD40-induced NF-{kappa}B signaling, characterized by enhanced I{kappa}B degradation and increased nuclear accumulation of p50-containing NF-{kappa}B complexes, despite reduced RelA stability. Mechanistically, we show that OTUB1 interacts with RelA, restricting its lysine-48-linked ubiquitination and proteasomal degradation, thereby stabilizing this key transcription factor. Collectively, these findings identify RelA as a novel OTUB1 target and uncover an additional layer of ubiquitin-dependent control of NF-{kappa}B signaling that governs splenic B-cell homeostasis and marginal zone B-cell development.

Chemical modifications of RNA, such as N4-acetylcytidine (acC), fine-tune gene expression, but their roles in cell fate determination within the immune system remain poorly understood. Here, we identify the RNA cytidine acetyltransferase NAT10 as a pivotal regulator of T follicular helper (TFH) cell differentiation and the germinal centre response. T cell-specific ablation of Nat10 in mice severely impaired TFH cell development, germinal centre formation, and antibody production following viral infection. Integrated epitranscriptomic and transcriptional profiling revealed that NAT10 deposits acC modifications on a cohort of mRNAs critical for immune function. We pinpointed the transcription factor TOX2 as a key downstream target, showing that acC modification within its mRNA coding sequence enhances both transcript stability and translation efficiency, thereby promoting TOX2 protein expression. Enforced TOX2 expression fully rescued the TFH differentiation defect in NAT10-deficient cells. This NAT10-acC-TOX2 axis is conserved in humans, where its activity correlates with the magnitude of vaccine-elicited TFH responses. Furthermore, we identified R428 as a potent NAT10 inhibitor and demonstrated that its administration could suppress pathogenic TFH responses and alleviate symptoms in a mouse model of allergic asthma. Our work elucidates a central epitranscriptomic mechanism controlling T helper cell fate and humoral immunity, and nominates NAT10 as a potential therapeutic target for TFH-driven diseases.

Tuberculosis (TB), the worlds deadliest infection, shows higher prevalence and mortality in males than females (M/F ratio >1.7). Using Four Core Genotype (FCG) mice to decouple gonadal from chromosomal sex (XX, XY gonadal males and XX, XY gonadal females), we show that gonadal males develop accelerated disease driven by dysfunctional myeloid responses rather than impaired bacterial recognition. Both XX and XY males exhibited increased mortality, higher Mycobacterium tuberculosis (Mtb) burden, and severe lung pathology. Mechanistically, gonadal male susceptibility involved early myeloid priming, excessive neutrophil recruitment, CCR2 monocyte accumulation, and hyperinflammation, with enhanced neutrophil extracellular trap (NET) formation and disorganized granulomas, implicating testes and androgens as key drivers of male susceptibility. While XY gonadal females were less susceptible, XX gonadal females showed the greatest resistance, associated with coordinated T- and B-cell responses and enhanced B-cell follicle formation. Together, these findings identify gonad-driven myeloid dysregulation as a central mechanism underlying male TB susceptibility.

Memory phenotype (MP) CD4+ T cells accumulate with age; however, the immunological significance of this population shift and the mechanisms that preserve MP T-cell fitness remain poorly understood. Here, we show that age-associated accumulation of MP T cells is regulated by intra-clonal competition and that competitive expansion of MP regulatory T (Treg) cells is required for maintenance of immune tolerance during aging. Using MLL1 deficiency as a model, we found that Mll1-deficient T cells failed to undergo normal age-associated accumulation and were progressively outcompeted by wild-type (WT) cells despite retaining the ability to proliferate and generate MP populations in the absence of competitors. Mechanistically, MLL1 preserved competitive fitness by maintaining transcription of TCR variable region genes and sustaining T-cell receptor expression during proliferation. Loss of competitive fitness impaired MP Treg-cell expansion and disrupted immune homeostasis. Remarkably, a small population of WT Treg cells restored tolerance through extensive expansion of MP Treg cells. These findings identify competitive expansion of MP Treg cells as a critical mechanism for maintaining immune tolerance during aging.

Biological sex can profoundly influence the susceptibility to infectious diseases, yet the mechanisms behind the sex-dependent protective immunity against tuberculosis (TB) remain poorly understood. Here we show that sexually divergent immunity during chronic Mycobacterium tuberculosis (Mtb) infection is governed by both intrinsic T cell programming and pulmonary immune spatial organization. Using the Four Core Genotype (FCG) mouse model, adoptive cell transfer, pathway-specific blockade and B cell depletion, we demonstrate that CD4 T cells from gonadal females (XXF), but not XX males (XXM), confer enhanced protection to susceptible XY male recipients, independently of sex chromosome complement. Female-derived CD4 T cells reduce Mtb burdens while promoting pulmonary Bcl6 CD4 T cell responses and limiting neutrophilic inflammation. Mechanistically, blockade of CXCR3 or CD40L abrogates female-associated protection, with CD40L signaling additionally required to maintain organized pulmonary B cell structures. Although depletion of conventional B-2 B cells did not impair bacterial control, it disrupted tertiary lymphoid organization and revealed striking sex-specific functions of pulmonary B cells. Loss of B cell follicles (BCFs) primarily remodeled adaptive T cell responses in females, whereas in males it drove inflammatory myeloid activation, exaggerated neutrophil recruitment and widespread neutrophil extracellular trap (NET) formation. Together, these findings identify two complementary layers of sex-dependent immune regulation during TB: intrinsic programming of protective female CD4 T cells, and B cell-dependent spatial organization that coordinates adaptive immunity in females while restraining pathological inflammation in males. These findings establish immune tissue organization as a key determinant of the sexually dimorphic host defense during chronic TB.

{gamma}{delta} T cells are promising mediators of cancer immunotherapy, yet their potential to drive autoimmunity remains incompletely understood. Here, we identify a feedback mechanism in which innate-like V{gamma}1.1V{delta}6.3 T cells are reprogrammed into ILC1-like cells, thereby restraining autoimmune pathology. We define a previously unrecognized ILC1 subset whose development depends on an intact Tcrd locus. These cells predominantly harbor productive V{gamma}1.1 and V{delta}6 rearrangements, consistent with their origin from V{gamma}1.1V{delta}6.3 T cells. Mechanistically, TCR signaling induces Id3, which suppresses E protein-dependent activation of T cell-specific genes, including that encoding V{delta}6.3. Id3 ablation drives robust expansion of V{gamma}1.1V{delta}6.3 T cells and severe autoimmunity, characterized by tissue infiltration, autoantibody production, enhanced T follicular helper cell differentiation, and accumulation of germinal center and age-associated B cells. Together with previously described exocrine dysfunction, these features resemble human Sjogrens disease. Consistent with this, we observed in the salivary glands of Sjogrens disease patients an increased frequency of CD4-CD8- T cells enriched for {gamma}{delta} T cells, including subsets functionally analogous to murine V{gamma}1.1V{delta}6.3 cells. Collectively, these findings uncover a TCR-Id3-dependent reprogramming pathway that limit the pathogenic potential of harmful {gamma}{delta} T cells.

The insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is a known N6-methyladenosine (m6A) reader, but its role in antiviral innate immunity is unknown. Here, we identify IGF2BP3 as a critical positive regulator of antiviral responses. Viral infection and interferon (IFN) stimulation upregulate IGF2BP3, establishing a feedforward loop that potentiates virus-induced activation of the TBK1-IRF3 and NF-{kappa}B pathways, thereby amplifying type I interferon (IFN-I) production, and restricting viral replication in human and murine cells and in vivo. Mechanistically, IGF2BP3 directly binds and stabilizes MAVS and TBK1 mRNAs and promotes their translation by facilitating recruitment to the eIF4F/PABP-associated initiation complex. Upon infection, IGF2BP3 relocalizes to antiviral stress granules (avSGs), where it scaffolds the RIG-I-G3BP1 complex to enhance viral RNA sensing. Notably, IGF2BP3 is aberrantly upregulated in patients with systemic lupus erythematosus (SLE) and in Trex1 knockout (KO) mice, and pharmacological inhibition by curcumol suppresses IFN-I-driven pathology and improves survival. Collectively, our findings establish IGF2BP3 as a central feedforward circuit that couples viral RNA sensing to the control of RNA stability and translation of key signaling molecules, and reveals its potential as a therapeutic target in interferon-associated autoimmune diseases. Significance StatementAntiviral immunity demands rapid and coordinated gene expression, yet how RNA-binding proteins link viral recognition to downstream signaling is poorly understood. We reveal that the m6A reader IGF2BP3 acts as a central amplifier of antiviral innate immunity. Induced by both viruses and interferons, IGF2BP3 enhances viral RNA sensing, stabilizes key signaling transcripts, and boosts their translation, creating a self-reinforcing feedforward circuit that strengthens interferon responses. Beyond host defense, IGF2BP3 is aberrantly elevated in interferon-driven autoimmunity, and its pharmacological inhibition reduce disease pathology in vivo. Our findings uncover a previously unrecognized mechanism that integrates RNA metabolism, stress-granule signaling, and translational control to regulate innate immunity, offering new therapeutic perspectives for both infectious and autoimmune disease.

The X-linked G-protein coupled receptor GPR174 is highly expressed in T and B lymphocytes and has immunoregulatory roles in mice, but its function in humans is unknown. We describe a cohort of six individuals who have function-disrupting variants in GPR174 and a clinical phenotype of lymphadenopathy and autoimmunity. Histological analysis of two patient lymph nodes revealed necrotizing lymphadenitis and lymphoproliferation resembling Kikuchi-Fujimoto disease. In-depth analysis of three patients and related carriers revealed overaccumulation of CD8 terminally differentiated effector memory cells re-expressing CD45RA (TEMRA). Patient cells and GPR174-deficient CD8 T cells generated from controls showed less repression of proliferation by the GPR174 ligand lysophosphatidylserine (lysoPS) and an effector-biased gene expression program. GPR174-deficient CD4 T cells were resistant to lysoPS-mediated suppression of IL2 production. In mice, chronic viral infection led to over-accumulation of GPR174-deficient effector CD8 T cells. We describe an inborn error of immunity associated with dysregulated lymphocyte responses that we propose predisposes to exaggerated lymphoproliferation and autoimmunity following viral infection.

Neutrophil recruitment into inflamed tissues requires coordinated transmigration across the multilayered venular wall, yet how this process is regulated beyond the endothelium remains poorly understood. Here, we identify a previously unrecognized platelet-neutrophil circuit that controls this post-endothelial phase. Intravital microscopy of inflamed cremasteric venules showed that pioneer neutrophil transmigration enabled platelet entry into the sub-endothelial compartment of venular walls. There, platelets became activated and released CXCL7 in a GPVI- and GPIb-dependent manner, generating spatially confined chemokine microdomains. These platelet-derived cues directed follower neutrophil migration and promoted their exit across the pericyte layer into the interstitial tissue. Collectively, these findings identify extraluminal platelets as spatial organizers of neutrophil trafficking and uncover a localized intramural feedback mechanism in which neutrophils amplify their own recruitment within venular walls. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/739803v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@19274dorg.highwire.dtl.DTLVardef@163659forg.highwire.dtl.DTLVardef@a4d063org.highwire.dtl.DTLVardef@6d4a47_HPS_FORMAT_FIGEXP M_FIG C_FIG

Early control of viral infection is thought to rely on pattern-recognition receptors (PRRs) that induce interferons (IFNs) and leukocyte recruitment, but how distinct PRRs coordinate mucosal antiviral defense remains unclear. We show that both the DNA-sensing cGAS/STING pathway and the RNA-sensing RLR/MAVS pathway are required for protection upon genital herpes simplex virus type 2 (HSV-2) infection. cGAS deficiency increased infection-induced pathology in both epithelial and submucosal compartments, whereas MAVS deficiency primarily affected the epithelium. Spatial proteomics and regional transcriptomics revealed that cGAS was essential for early epithelial TBK1 activation, expression of IFN-stimulated genes and recruitment and activation of myeloid and lymphoid cells to the epithelium. While MAVS was essential for full TBK1 activation it had limited impact on the induced IFN response. However, MAVS sustained basal epithelial expression of the antiviral factors IFITM1 and 3, which exert antiviral activity against HSV-2. Notably, cGAS deficiency impaired submucosal IFN responses and enabled viral spread into this tissue, enabling infection of intervening neurons and dissemination to the central nervous system. These findings define coordinated, compartment-specific innate defense against infections.