Dengue causes over 390 million annual infections globally. Qdenga (TAK-003), the only widely available dengue vaccine, has an incompletely defined immunological profile. We performed longitudinal immunological profiling of 110 adults from a dengue-endemic region, including older adults (≥65 years), to assess the effects of immune imprinting and vaccine design on humoral and cellular immunity. Qdenga elicited B and T cell activation across groups but generated serostatus-dependent, serotype-skewed antibody responses. Only 8% of DENV-naïve individuals developed tetravalent neutralizing responses, whereas one-third responded to a single serotype, predominantly DENV-2, the vaccine backbone. DENV-exposed individuals mounted broader responses shaped by preexisting immunity, yet DENV-4 neutralization remained consistently poor. Neutralizing antibody titers plateaued after the first dose, with no increase following the second. These findings clarify why balanced tetravalent immunity is rarely achieved with Qdenga and demonstrate that both immune imprinting and vaccine backbone limit the breadth and magnitude of the responses. This has important implications for deployment, long-term protection in naive populations, and DENV-4-targeted boosters.
Neural implants are limited by the foreign body response, a protective but often unresolved reaction culminating in reactive gliosis and signal instability. We propose that long-term implant instability arises from progressive erosion of lineage-defining regulatory programs, uncoupling cellular compensation from tissue needs.
Myeloid cells play crucial roles in cancer progression, influencing tumor growth, metastasis, and response to immunotherapy. The mechanisms shaping their diverse functions in the tumors remain poorly understood and may offer therapeutic opportunities. Here, we identify the lipid-presenting molecule CD1d as a regulator of tumor progression and myeloid heterogeneity in the tumor microenvironment. Using several mouse models of breast cancer, we demonstrate that genetic deletion or antibody-mediated targeting of CD1d leads to reduced tumor growth, altered immune infiltration, and improved efficacy of anti-PD-1 immunotherapy. Specifically, CD1d targeting reshapes the intratumoral myeloid compartment, enhancing proinflammatory programs and resulting in accumulation of inflammatory monocytes. The CD1d-dependent control of myeloid cell functional differentiation is cell-intrinsic and conserved in human and mouse. Through single-cell RNA sequencing, we define the transcriptional landscape associated with CD1d deficiency and derive a gene signature that correlates with clinical outcomes and response to immunotherapy in breast cancer patients. Thus, CD1d could provide a potential target to alter tumor-infiltrating myeloid populations and enhance immunotherapy responses.
The first approval of malaria vaccines RTS,S/AS01 and R21/Matrix M marked a major milestone. Both vaccines present a portion of the Plasmodium falciparum circumsporozoite protein (PfCSP) containing an immunodominant major repeat region, which may limit breadth to other protective epitopes, limiting efficacy and durability. Using B cell receptor (BCR) knock-in mice, we found that the R21-included PfCSP epitope elicited robust B cell responses to the immunodominant major repeats but not to other highly protective epitopes, the minor repeat and junction. We then defined a minimal peptide capable of eliciting minor repeat-specific B cell responses and generating highly protective antibodies (Abs). We characterized these Abs bioinformatically and structurally to identify protective traits, which informed the design of variant Abs with improved affinity. Finally, we demonstrated that vaccination combining the R21-included PfCSP epitope, the minimal minor repeat peptide, and a junctional region immunogen elicited balanced B cell and Ab responses, enhancing protection in vivo. Broadening responses through immunofocusing may overcome immunogenic gaps in current malaria vaccines.
Immune memory responses are rapid and qualitatively distinct from primary responses. They typically develop in the presence of antigen-experienced memory T and B cells and preexisting antibodies. Although the contribution of T and B cells to recall responses is well defined, the contribution of antibody “memory” and the mechanisms by which preexisting antibodies modulate the development of germinal center (GC) and plasma cell responses is not precisely understood. Here, we report on mechanisms that mediate antibody enhancement of GC and plasmablast (PB) compartments, and the parallel process by which antibodies change the affinity threshold for B cell recruitment into immune responses. The data indicate that antibody-mediated enhancement of GC and PB responses is Fc gamma receptor (FcγR) dependent and largely complement receptor 1 and 2 (CR1/2) independent. In contrast, the reduction in the affinity threshold for GC entry is independent of both FcγRs and CR1/2.
Therapeutic blocking antibodies against TNF-like cytokine 1A (TL1A) are emerging as one of the most compelling targets in inflammatory bowel disease (IBD). Preliminary phase 2 studies using TL1A-blocking antibodies have demonstrated some of the highest response rates seen in UC and CD. As the field waits for definitive phase 3 study results, the first of which are expected this summer, mechanistic data continue to expand the biological scope of TL1A in IBD.
A high-affinity antibody response to both infection and vaccination critically relies on the ability of B cells to capture and process antigen for presentation to CD4+ T cells. The cellular processes from antigen recognition to full B cell activation require a finely orchestrated series of events, involving signalling and intracellular trafficking mechanisms. Here, we describe a novel regulator of B cell receptor (BCR) endocytosis and intracellular trafficking. Multidomain trafficking protein sorting-related receptor with A-type repeats (SorLA) associates with the BCR and regulates uptake of both soluble and substrate-bound antigens. SorLA deletion results in altered BCR-antigen intracellular trafficking to degradative compartments, modulating eventual antigen presentation. Crucially, this change in antigen trafficking results in a significant reduction in plasma cells and humoral responses in vivo. Given the critical importance of antigen presentation in immunity, as well as autoimmune disease and malignancy, these results identify a new cellular pathway in B cell biology with potential implications for immune regulation.
Antibody-drug conjugates (ADCs) have become an increasingly important component of the therapeutic landscape of many solid tumors. Currently, there are eight ADCs approved for solid tumors, with hundreds being developed and in clinical trials. Initially being approved in the advanced or metastatic settings, ADCs are also being incorporated as neoadjuvant or adjuvant therapies. In this review, we discuss the important components of ADC design in the context of clinical successes and failures. We further evaluate mechanisms of intrinsic and acquired resistance and strategies to overcome these barriers. Finally, we discuss the landscape of potential combination partners to increase efficacy of ADC therapies.
We previously reported inherited retinoic acid-related orphan receptor γ T (RORγT) deficiency in seven patients from three ancestries (Chilean, Palestinian, and Saudi Arabian) with mycobacterial disease and chronic mucocutaneous candidiasis (CMC). We report here five additional patients from different ancestries (Afghan, Indian, Iranian, Japanese, and 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 mucosa-associated invariant T and invariant natural killer T cells, low counts of adaptive TH1* and CD8+ T cells, and impaired Mycobacterium-induced IFN-γ production by the remaining cells of these subsets, NK cells, conventional CD4+ T, Vδ1, and Vδ2 γδT cells. Most patients also displayed CMC due to their low counts of TH17 and TH1* cells. One patient died from disseminated Bacille Calmette-Guérin vaccine infection, but, unexpectedly, all the other patients are still alive and clinically stable at ages of 2 to 20 years. RORγT is essential for protective immunity against mycobacteria and Candida in humans.
Invasive Candida albicans infections (candidiasis) cause progressive organ damage through fungal tissue invasion and toxin-mediated injury, including in the kidney. Hyphal invasion induces apoptosis of renal tubular epithelial cells (RTEC), a key driver of kidney pathology, yet intrinsic renal protective mechanisms remain poorly defined. We identify fibrinolytic tissue-type plasminogen activator (tPA) as a critical mediator of renal tissue protection in candidiasis. tPA is induced by IL-17 and TNFα in renal endothelial cells and RTEC. tPA signals through low-density lipoprotein receptor-related protein 1 (LRP1) and activates ERK1/2 signaling to suppress apoptosis in RTEC. Mice with RTEC-specific deletion of LRP1 exhibited exaggerated kidney damage during candidiasis. Administration of a nonenzymatic form of tPA recapitulated the protective effect of tPA by limiting RTEC apoptosis. These findings reveal the role of tPA/LRP1 axis in preserving renal integrity in candidiasis and suggest clinically approved tPA as a potential therapeutic strategy to mitigate candidiasis-associated tissue injury.
IL-17 is well-recognized for orchestrating mucosal antifungal immunity. In this issue of JEM, Choi et al. (https://doi.org/10.1084/jem.20260530) identify a downstream tPA-LRP1 axis that safeguards the renal epithelium during systemic candidiasis, revealing a mechanism by which IL-17 preserves organ integrity.
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.
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.
The clearance of apoptotic cells by phagocytes is crucial for restoring tissue balance after injury. In autoimmune liver diseases like primary sclerosing cholangitis, cell death is thought to result from accumulation of toxic bile acids within parenchymal cells. Whether, in this context, bile acid-loaded dying cells impact the efficiency of phagocytic macrophages in restoring tissue balance remains unknown. Here, we demonstrate that in a murine model of cholangitis, bile acids accumulate in a subpopulation of efferocytic macrophages with pro-inflammatory features. Our in vitro results indicate that, upon their engulfment, apoptotic hepatocytes laden with bile acids can serve as Trojan horses, delivering bile acids into efferocytic macrophages and thereby shaping macrophage function. This contrasts with the characteristics of macrophages that engulf apoptotic parenchymal cells lacking bile acids. Together, our findings delineate a system in which the content of the phagocytosed dying cells, specifically bile acid-laden hepatocytes, drives a pro-inflammatory program in the corresponding efferocytic macrophages, potentially contributing to chronic hepatic inflammation.
Long-term maintenance of immune memory is critical for the control of recurring virus infections and cancer. In this issue of JEM, Ma et al. (https://doi.org/10.1084/jem.20252687) report that the E2 ubiquitin-conjugating enzyme UBE2F restrains long-term CD8 T cell memory.
