Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.

Homozygosity for rare loss-of-function IL23R variants abolishes IL-23-dependent IFN-γ production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12Rβ1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-γ production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria.

Recent evidence implicates altered RNA editing and dysregulated type I IFN signaling in immune-mediated diseases, including psoriasis, although the underlying genetic mechanisms remain poorly defined. We investigated four unrelated multiplex families with early-onset plaque psoriasis, with or without psoriatic arthritis, segregating as a monogenic trait and characterized by a strong IFN signature in skin and blood. Whole-exome sequencing identified four rare heterozygous loss-of-function mutations in ADAR1 cosegregating with disease and elevated IFN-stimulated gene expression. Six additional rare variants were detected in an independent cohort of 125 psoriasis patients. Single-cell transcriptomics identified keratinocytes and melanocytes as major IFN sources. Functional studies showed that ADAR1 knockdown or expression of ADAR1G1119R and ADAR1P3A alleles pathogenic variants reduced adenosine-to-inosine RNA editing and increased IFN-stimulated genes and inflammatory cytokines, effects reversed by upadacitinib and deucravacitinib. These findings define a novel IFN-dependent psoriasis subtype caused by inborn defects of ADAR1-mediated RNA editing, with direct implications for precision medicine in psoriatic disease.

CD137 is expressed in a subset of Foxp3+ regulatory CD4 T cells (Tregs), but its immunoregulatory role is not fully defined. Due to alternative splicing that removes the transmembrane domain-encoding exon, CD137 exists in both membrane and soluble forms. We investigated the function of CD137 in Foxp3+ Tregs using the NOD mouse model of type 1 diabetes (T1D). Foxp3+ Treg-specific deletion of CD137 reduced circulating soluble CD137 and accelerated T1D development, driven by heightened clonal expansion and differentiation of effector T cells in pancreatic islets. CD137 deficiency in Foxp3+ Tregs reduced their frequency in islets and impaired their differentiation toward a suppressive phenotype. Restoring soluble CD137 in Foxp3+ Tregs lacking its membrane form reduced islet T cell activation and mitigated T1D acceleration without altering the accumulation of suppressive Foxp3+ Tregs. Our results indicate that both soluble and membrane forms of CD137 expressed by Foxp3+ Tregs are critical for immunoregulation, and they independently restrain T1D development.

The nervous system has emerged as a critical regulator of cancer progression. Recent studies demonstrate that peripheral neurons shape tumor growth, dissemination, and therapeutic response by regulating multiple components of the tumor microenvironment. In parallel, tumors within the body remodel their neural niche by recruiting innervation and modulating neuronal phenotype and activity. This bidirectional cross talk positions neural circuits as integral components of the tumor ecosystem, linking environmental cues, including metabolic stress, inflammation, and the impact of treatment, to coordinated multicellular responses that promote progression and treatment resistance. Here, we review the field of cancer neuroscience with a focus on solid tumors originating outside the central nervous system. We synthesize mechanistic insights into how the peripheral nervous system shapes the tumor microenvironment to influence tumor behavior and highlight emerging therapeutic opportunities to target neural pathways. Together, these findings identify the nervous system as an upstream regulator of cancer biology and a tractable target for intervention.

Type III IFNs, or IFNλ, are pleiotropic immune mediators that mostly work at mucosal surfaces by signaling in epithelial cells and selected immune cells. Zhou, Zhang, and colleagues (https://doi.org/10.1084/jem.20251858) demonstrate that IFNλ also signals in kidney fibroblasts sustaining renal fibrosis.

In this issue of JEM, Schroeder et al. (https://doi.org/10.1084/jem.20251959) report that the transcription factor BACH2 has context-dependent dual functions in regulating the differentiation of follicular T helper cells.

Meningeal lymphatic vessels within the dura provide a route for cerebrospinal fluid (CSF) outflow, but how CSF crosses the arachnoid barrier, particularly toward basal dural compartments, remains unclear. Using in vivo CSF tracer infusion and ultrastructural analysis in mice, we show that bridging vein-associated arachnoid cuff exit (ACE) domains provide specialized routes for CSF movement from the SAS into the dura. These ACE-associated structures are abundant in the basal than dorsal meninges, supporting preferential CSF efflux toward basal meningeal lymphatics. In contrast, spinal meninges lack comparable ACE structures, and spinal CSF exits along the nerve root arachnoid sleeves rather than entering the spinal dura. Depletion of parenchymal border macrophages stalls tracer movement, leading to retention within the subarachnoid and dural compartments, revealing their regulatory role in arachnoid-bypassing CSF drainage. These findings establish a compartmentalized CSF outflow model, in which basal bridging vein-associated ACE structures serve as major dural exit portals, with dorsal limitation and spinal exclusion.

Asthma is a deadly chronic respiratory disease affecting over 300 million people. While allergen immunotherapy remains the only disease-modifying treatment, it is poorly applicable for patients with severe asthma. Here, we explored the therapeutic potential of regulatory T cells (Tregs) armed with chimeric allergen receptors-named CAlleR-redirected against the major allergen of birch pollen Bet v1. Four novel anti-Bet v1 antibodies were identified and used to engineer and functionally validate CAlleR. CAlleR Tregs showed specific in vitro activation and suppression and significantly reduced the airway hyperresponsiveness in birch pollen-sensitized mice. Mechanistically, CAlleR Tregs migrated to the lungs and mediastinal lymph nodes, interacted with CD11c+ dendritic cells, and were activated in a FcγR-dependent manner by cross-presenting Bet v1 stabilized with noncompetitive anti-Bet v1 antibodies. These findings unveil a novel mechanism for targeting soluble antigens and highlight the potential of CAlleR Tregs to prevent and treat severe allergies.

Renal fibrosis is a critical step in chronic kidney disease (CKD) progression, but fibrosis induction is still not understood well. We found that IFN-λ is a profibrotic factor that is upregulated in fibrotic human and mouse kidneys. IFN-λ receptor deficiency ameliorated renal fibrosis in mice while exogenous IFN-λ exacerbated disease, establishing a detrimental role of IFN-λ signaling in renal fibrosis. Mechanistically, we found that IFN-λ promotes fibrosis by preferentially acting on renal fibroblasts, inducing their activation and migration through ERK/JNK-dependent synthesis of TGF-β and activation of the TGF-β-SMAD2/3 signaling pathway. Renal tubular epithelial cell (TEC)-derived IFN-λ induced by RIG-I/MAVS signaling emerged as a critical driver of renal fibroblast activation and fibrogenesis. Importantly, neutralizing antibodies against IFN-λ strongly attenuated renal fibrosis in mice. Thus, the renal TEC-IFN-λ-fibroblast axis is a previously unrecognized pathway of renal fibrosis induction that represents an attractive novel target for mitigating CKD progression.

Intravesical therapies are the mainstay of bladder cancer (BCa) management, but their efficacy is limited by toxicities and recurrences. While CAR T cell therapy has shown promise in hematologic malignancies, its application in solid tumors is limited by poor trafficking and on-target off-tumor toxicities. Here, we identify and validate MUC16 as a clinically relevant target for BCa, noting enriched expression in tumors recalcitrant to existing therapies. We engineered a second-generation mesothelin-based CAR (MSLN-28z) and demonstrated robust activity across multiple BCa cell lines and patient-derived tumor organoids. Intravesical delivery of MSLN-28z CAR T cells in xenograft BCa models conferred superior tumor control compared with intravenous transfer, while attenuating systemic T cell engraftment. Intravesical adoptive transfer uncouples local antitumor efficacy from potential systemic toxicity-a feature conserved across several T cell immunotherapies with on-target off-tumor activity. Collectively, these findings substantiate MUC16 as a therapeutic candidate and validate intravesical delivery as a platform for T cell immunotherapies in the management of organ-confined BCa.

B-T cell cross talk is safeguarded by central and peripheral tolerance and cell-intrinsic checkpoints. In this issue of JEM, Lin et al. (https://doi.org/10.1084/jem.20251968) show that altered translation in early germinal center B cells triggers a vicious cycle of aberrant B-T cell interactions culminating in lymphomagenesis.

Mechanical forces are increasingly recognized as potent regulators of inflammation. Physical cues such as stretch, tissue stiffness, and shear stress shape innate immune responses across barrier epithelia, stromal niches, and the vascular endothelium. By engaging conserved mechanotransduction pathways, these forces both modulate and initiate mechano-inflammatory programs, remodeling immune synapses, reconfiguring tissue architecture, and directing leukocyte trafficking. When tissue mechanics are chronically perturbed through sustained pressure, matrix remodeling, or disturbed flow, these same pathways drive pathological inflammation and contribute to diseases ranging from asthma and arthritis to fibrotic disorders and atherosclerosis. In this review, we position mechano-inflammation as a unifying framework linking physical forces to immune regulation. We also highlight diagnostic and therapeutic opportunities targeting the mechanical dimension of immunity.