ImmunoHorizons最新文献

Respiratory syncytial virus (RSV) is a major global cause of severe lower respiratory tract infections in infants and older adults. RSV has 2 subgroups, A (RSV-A) and B (RSV-B), which circulate together with different patterns of dominance. A vaccine must protect against both. Reccently, prefusion F protein-based vaccines for maternal and older adult populations achieved ∼70% efficacy, and Moderna's mRNA vaccine for older adults further underscores the potential of mRNA platforms. Here, we report preclinical evaluation of VER-027, a novel mRNA vaccine encoding prefusion F proteins from both RSV-A and RSV-B. A 2-dose intramuscular regimen induced high pre-F-specific immunoglobulin G (IgG) titers, potent neutralizing activity against both subgroups, and robust F85-93-specific CD8+ T cell responses. All mice vaccinated with this mRNA vaccine were fully protected against RSV-A and RSV-B challenge. These findings support VER-027 as a strong candidate for clinical development as a dual-subgroup RSV vaccine.

Natural killer (NK) cell function within tissues extends beyond exerting cytotoxicity, encompassing a range of functions that are just starting to become fully elucidated. In the context of human placentation, NK cells play a key role in enabling initial placentation, which is associated with the acquisition of tolerance-like properties. If and to which extent NK cells maintain these tolerance-like properties over the course of human pregnancy is still poorly understood. We asked if NK cells isolated from the decidual-placental interface of full-term human pregnancies are able to exert effector function. We observed a significant and striking lack in the ability of NK cells isolated from the decidual-placental interface (DPI) to produce interferon-g (IFN-γ) in response to the activating cytokines interleukin (IL)-12, IL-15, and IL-18. In contrast, NK cells from the decidua retained their responsiveness to cytokine-mediated activation. Notably, CD103+CD69+ tissue-resident NK cells were present in both DPI and decidua, yet exhibited distinct effector function from one another. Using high-parameter flow cytometry and single-cell sequencing, we found that this functional discrepancy was not directly predictable based on their cell surface phenotype or cell transcript. Together, our findings reveal the presence of distinct functional resident NK cell populations in 2 anatomically adjacent tissues at healthy full-term pregnancies.

During thymocyte development, positive selection produces cells whose T cell receptors (TCRs) bind to self MHC. Then, negative selection culls most thymocytes whose TCRs have too high an affinity for self MHC+peptide. Signal transduction events control these processes. CD8-αβ (via CD8-β) recruits p56lck to the immunological synapse and promotes signaling through the TCR. Conversely, PD-1 attenuates TCR signal transduction. We examined the roles of CD8-β and PD-1 in the survival of thymocytes in H-2k haplotype mice expressing a transgenic BM3 TCR, which has high affinity for the allogeneic H-2Kb MHC I molecule. In transgenic mice expressing both H-2Kb in the thymic medulla and the BM3 TCR, apoptosis eliminates most (but not all) post-selection thymocytes. To analyze the roles of CD8-β and PD-1 in the survival of post-selection thymocytes, we devised a novel probabilistic gating strategy employing Gaussian mixture models and statistical methods using sliding windows and changepoint detection. We found that at high levels of CD8-β and therefore high levels of CD8-αβ), thymocytes are prone to apoptosis, regardless of the PD-1 level. At intermediate levels of CD8-β, thymocyte survival increases concordantly with increasing PD-1 levels. At low levels of CD8-β, thymocyte survival is high regardless of the PD-1 level. Surviving DPlo post-selection thymocytes give rise to PD-1+CCR7+DN and PD-1+CCR7-DN post-selection thymocytes, which appear to become DN T cells and IELs, respectively. Thus, PD-1 appears to promote the survival of both IEL precursors and thymocytes destined for other fates. More strikingly, downregulation of CD8-β is a hallmark of autoreactive MHC I-restricted thymocytes that survive negative selection.

Macrophages are central players of inflammation, lipid metabolism, and remodeling in atherosclerotic plaques. Historically simplified into "M1" and "M2" polarization states, their biology has been fundamentally redefined by single-cell and spatial transcriptomic technologies. Over the past decade, these approaches have identified multiple macrophage subsets within human atheromas, each driven by distinct metabolic and cytokine signatures and occupying discrete spatial niches. Human single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and multimodal omic profiling collectively demonstrate that macrophage subsets extend far beyond fixed polarization states to engage their long-recognized functions in the atheroma, including inflammation, lipid handling and repair. These findings now link macrophage identity to microenvironmental cues, vascular location, and disease stage. Importantly, these data demonstrate that these macrophages do not exist in mutually exclusive states and can transition between these subtypes in response to these aforementioned factors. Here we synthesize these advances, focusing on human data describing macrophage diversity, spatial organization, and metabolic function, and discuss how this knowledge is reshaping mechanistic models of atherosclerosis and the potential therapeutic targeting of macrophage-mediated pathology.

Cardiovascular disease (CVD) remains the leading cause of death worldwide, despite significant progress in identifying and managing traditional risk factors such as hyperlipidemia, hypertension, and diabetes. While targeted therapies addressing these factors reduce the risk of primary and secondary cardiac events, a substantial "residual risk" persists even after successful clinical intervention. This residual risk has prompted renewed interest in understanding the long-term biological effects of cardiovascular risk factors, particularly through the lens of chronic inflammation. Recent advances highlight a pivotal role for trained immunity-a form of innate immune memory driven by epigenetic and metabolic reprogramming-in driving this inflammation. Unlike adaptive immune memory, trained immunity occurs in innate immune cells and enhances their responsiveness to subsequent, unrelated stimuli. Emerging evidence suggests that various cardiovascular risk states, including hypercholesterolemia, obesity, and diabetes, can induce trained immunity, leading to heightened inflammatory tone that persists over time. Cardiac macrophages, as central mediators of tissue homeostasis and inflammation in the heart, are increasingly recognized as critical targets of this phenomenon. In this review, we explore how established cardiovascular risk factors can induce trained immunity on cardiac macrophages and examine the implications for disease progression, myocardial remodeling, and post-injury repair. Finally, we discuss emerging therapeutic strategies aimed at modulating trained immunity to reduce residual cardiovascular risk, offering a new frontier in the prevention and treatment of CVD.

Cardiovascular diseases (CVDs) account for millions of deaths worldwide each year, underlining their significant impact on global health. An expanding body of evidence identifies atherosclerosis, myocardial infarction, heart failure, and ischemic stroke as major contributors to this burden. Central to the pathogenesis of these conditions is the inflammatory response-a key defense mechanism that, when dysregulated, accelerates disease progression and disrupts cellular homeostasis, ultimately leading to adverse clinical outcomes. Efficient resolution of inflammation is essential not only for halting the inflammatory responses but also for restoring tissue integrity. One critical aspect of resolving inflammation is the efficient clearance of apoptotic cells, a process known as "efferocytosis," which remains underappreciated. Cardiac macrophages are tasked with removing apoptotic cells, necrotic cells, and cellular debris through efferocytosis. Importantly, recent studies have demonstrated that efficient efferocytosis is associated with improved outcomes in CVDs, whereas impaired efferocytosis perpetuates inflammation and hinders recovery. This tightly regulated mechanism not only resolves inflammation by suppressing proinflammatory cytokines but also stimulates the production of anti-inflammatory cytokines and reprograms macrophages to promote tissue homeostasis. This mini-review consolidates current understanding of macrophage efferocytosis and its molecular mechanisms, providing valuable insights into cardiac health and highlighting its significant potential as a therapeutic avenue for treating CVDs.

Chronic low-grade inflammation is a hallmark of atherosclerosis and cardiovascular diseases, with monocytes playing a central role in sustaining this pathological state. In this study, we demonstrate that prolonged exposure to oxidized low-density lipoprotein (oxLDL) or cholesterol reprograms murine bone marrow-derived monocytes into a persistent pro-inflammatory phenotype. This is characterized by elevated surface markers (CD49d, CD74, CD38, CD86), enhanced endothelial and T cell interactions, and sustained activation of the Src-SYK-mTORC1-STAT3/5 signaling axis. Notably, the inflammatory state persisted even after stimulus withdrawal, suggesting the establishment of an immune memory-like phenotype. Mechanistically, we defined the membrane clustering of Src is responsible for the generation of intra-cellular stress signaling and sustained monocyte activation, which can be alleviated by the administration of fumagillin, a selective inhibitor of protein myristoylation and Src membrane clustering. Our findings uncover mechanistic insights into the generation of sustained monocyte low-grade inflammatory memory and pinpoint potential therapeutic strategies in erasing low-grade inflammation related to chronic diseases.

Kidney transplant recipients (KTRs) exhibit impaired immune responses to vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, remaining vulnerable to severe coronavirus disease 2019 (COVID-19) even after multiple vaccine doses. We hypothesized that repeated SARS-CoV-2 vaccinations in KTRs might promote remodeling of the adaptive immune repertoire. In order to address this hypothesis and gain insight into adaptive immune dynamics in this population, we employed next-generation sequencing (NGS) to determine longitudinal alterations in immunoglobulin (IG) and T cell receptor (TR) gene repertoires following multiple mRNA vaccinations and functional experiments to assess lymphocyte signaling capacity. TR gene repertoire analysis revealed increased diversity and reduced clonality after booster immunizations, indicative of substantial repertoire renewal. Although the relative frequency of SARS-CoV-2-specific TR clonotypes remained stable over time, significant shifts in TRBV gene usage reflected dynamic reshaping of the TR clonal architecture. Parallel IG gene repertoire profiling demonstrated increased diversity and limited oligoclonal expansions after booster mRNA vaccination. These changes were accompanied by elevated levels of somatic hypermutation in IG clonotypes similar to published SARS-CoV-2-specific clonotypes, suggestive of more efficient humoral responses following repeated antigenic exposure. Phospho-specific flow cytometry analysis revealed initially diminished B cell receptor signaling, which was restored following multiple immunizations, consistent with reversal of B cell anergy status. Altogether, our findings support the notion that repeated SARS-CoV-2 vaccinations drive the remodeling of cellular and humoral immune landscapes in KTRs. These results underscore the importance of tailored vaccination strategies to optimize immune protection in immunocompromised individuals.

Aberrant angiogenesis in ovarian cancer (OC), driven by excessive vascular endothelial growth factor (VEGF) and other proangiogenic mediators, gives rise to structurally and functionally abnormal tumor vasculature that hinders effective T-cell infiltration. To overcome these barriers, we investigated how modulation of the perivascular niche influences antitumor T-cell trafficking and function in OC. T cells expressing a rearranged TCR transgene specific for SV40 T antigen (TAG) were adoptively transferred into TAG+ MOVCAR 5009 ovarian tumor-bearing SCID mice or syngeneic TgMISIIR-TAg-Low transgenic mice, which express TAG as a self-antigen in the fallopian tube epithelium. Transfers were performed either alone or following treatment with an oncolytic vaccinia virus expressing a CXCR4 antagonist (OV-CXCR4-A) or a control virus (OV-Fc). Compared with OV-Fc, OV-CXCR4-A treatment remodeled the tumor vasculature, inhibited recruitment of VEGF-producing myeloid-derived suppressor cells, and disrupted the proangiogenic microenvironment. These changes enhanced infiltration of adoptively transferred TCRTAG T cells within the perivascular niche, correlating with improved antitumor activity and survival. Collectively, our findings demonstrate that CXCR4 blockade-mediated reprogramming of the perivascular tumor microenvironment promotes effective T-cell trafficking and function, providing a mechanistic rationale for combining oncolytic virotherapy with adoptive cell transfer in OC.