ImmunoHorizons最新文献

The composition of the gastrointestinal microbiome is correlated with numerous immune-mediated systemic diseases, but underlying mechanisms remain unclear. In murine studies, we recently identified microbiome Bacteroidota-derived bacterial molecules, serine-glycine lipodipeptides (S/G lipids), as mediators of microbiome-systemic innate immune system crosstalk. By altering microbiome production of S/G lipids, we documented that proinflammatory responses of splenic monocytes could be regulated. Transcriptomic analysis revealed that this regulation occurred by modulating the mRNA levels of inhibitors of the TLR/NF-κB pathways such as Trem2. The present murine study had 2 goals: (1) to determine if our approach allows for modulation of activated innate immune cells, that is, macrophages rather than splenic monocytes, in a site of inflammation and (2) to document that our approach regulates cellular expression of the disease-relevant TLR/NF-κB pathway inhibitor, TREM2, at the protein level. We now report that decreasing microbiome-derived S/G lipid levels enhances proinflammatory responses and decreases expression of TREM2 in activated peritoneal macrophages (PMs). Furthermore, after lowering microbiome S/G lipid production, administering S/G lipids normalizes both PM proinflammatory responses and TREM2 expression. The harnessing of the microbiome and S/G lipids to modulate proinflammatory responses and TREM2 expression in activated innate immune cells suggests the therapeutic potential of this approach in inflammatory diseases such as Alzheimer's disease, atherosclerosis, autoimmunity and liver disease.

Memory-like natural killer (NK) cells with enhanced antibody-dependent cellular cytotoxicity (ADCC) have correlated with protection from uncomplicated malaria in prior studies. However, the role of NK cells in severe malaria (SM) has not been characterized. In Ugandan sites with moderate and low malaria transmission, we evaluated NK cell (CD56bright, CD56dim, CD56neg) phenotype and ADCC function by flow cytometry in children <5 years of age with SM (n = 21) and control community children (CC, n = 19). Children with SM had similar total NK cell counts to CC. Children with SM had a higher proportion of LILRB1+ NK cells than CC. The level of malaria transmission in an area was related to NK cell function. In the low malaria transmission area only, children with SM had a higher proportion than CC of NK cells that degranulated, whereas children with SM from both low and moderate malaria transmission areas had lower IFN-γ production than CC. We next evaluated functional Boolean gating for degranulation and IFN-γ production (CD107a+/IFN-γ-, CD107a-/IFN-γ+, and CD107a+/IFN-γ+) in relation to memory-like and checkpoint/exhaustion NK cell markers in low and moderate malaria transmission SM and CC groups. We found there was a significant increase in degranulating only NK cells (CD107a+, IFN-γ-) in children with SM compared to CC solely in the low malaria transmission area. However, there was a significant decrease in NK cells that produced IFN-γ but did not degranulate (CD107a-, IFN-γ+) in children with SM compared to CC in both low and moderate transmission areas. Our data reveal compound functional differences in NK cells among children with SM living in areas of low versus moderate malaria transmission; however, a consistent finding is reduced NK cell IFN-γ production in SM, regardless of transmission intensity.

Many scientists learn during training to use analysis of variance (ANOVA) when comparing more than 2 groups, yet the principles and follow-up steps are often not well explained. This overview provides a practical guide for selecting appropriate multiple comparisons tests and for interpreting and presenting data accurately. While not exhaustive, it highlights commonly used approaches, many of which are available in GraphPad Prism, a widely used statistical program among cell and molecular biologists. The authors have no affiliation with Dotmatics, the distributor of GraphPad Prism, and this overview is not intended as an endorsement of the software.

Naïve T cells are highly metabolically active, maintaining homeostatic function as well as continuously moving and surveying lymph nodes for dendritic cells (DCs) presenting cognate antigen. T-cell metabolism is thought to change throughout development: Naïve T cells have been found to predominantly utilize catabolism for naïve T-cell homeostasis while T-cell activation leads effector T cells to become glycolytic. There is still relatively less known about how individual and combinations of molecular signals drive specific metabolic programs in naïve T cells. Naïve T cells primarily depend on IL-7 signaling to IL-7R for homeostasis and are driven by the chemokine receptor CCR7 responding to CCL21 for rapid motility in lymph nodes, leading to T-cell surveillance. We identify specific roles for IL-7R and CCR7 in driving differential metabolic programs in naïve CD8+ and CD4+ T cells. We find that while IL-7 treatment increases glycolysis in both naïve CD4+ and CD8+ T cells, CCL21 treatment does not affect glycolysis. Instead, CCR7 signaling decreases respiratory capacity and mitochondrial intensity and area. While IL-7 treatment does not impact overall oxidative phosphorylation, IL-7 also alters mitochondrial dynamics. Interestingly, a combination of IL-7R and CCR7 signaling using IL-7 with CCL21 differentially affects CD4+ versus CD8+ T-cell metabolism. Our results demonstrate that multiple molecular signals can differentially regulate naïve CD4+ and CD8+ T-cell metabolism, leading to changes in both glycolysis and oxidative phosphorylation in naïve T cells.

Zoonotic spillover of influenza A viruses into humans has repeatedly triggered pandemics throughout history. Since their emergence in the 1990s, H5N1 influenza viruses have significantly expanded their geographical range and host species, raising global concern about the potential for sustained human-to-human transmission. In this review, we examine the virological characteristics of currently circulating H5N1 strains, key molecular barriers limiting their spread among humans, and critical areas of future research to mitigate the ongoing H5N1 panzootic and prevent future pandemics.

Highly pathogenic avian influenza (HPAI) poses an expanding global threat with direct relevance to immunologists studying host-pathogen dynamics, cross-species transmission, and immune responses to emerging viruses. Driven primarily by evolving H5 and H7 influenza A subtypes, HPAI now affects a broadening host range, including spillovers into mammals such as seals, cattle, and humans, raising concern for pandemic potential. Applying a One Health perspective, this review emphasizes the immunological and ecological factors that underlie HPAI emergence and spread. Migratory bird flyways, shared aquatic habitats, and intensive poultry systems create viral mixing zones that promote antigenic diversification and interspecies transmission. Climate change and land-use transformation exacerbate these risks by altering host distributions and increasing interfaces between wildlife, livestock, and people. While poultry vaccines are widely used, human vaccine development faces challenges from antigenic drift, clade variation, and limited cross-protective immunity. Immunologists play a critical role in understanding these dynamics, particularly regarding host immune barriers, viral adaptation, and the development of broad-spectrum or next-generation vaccines. Technological advances in pathogen surveillance, such as AI-driven forecasting, genomic sequencing, and real-time risk mapping, are promising early-warning tools, but require stronger integration across human, animal, and environmental health sectors. Addressing HPAI's complex immunoecological dynamics demands a One Health approach: cross-sectoral data sharing, coordinated response strategies, and investment in resilient health systems. As HPAI continues to evolve and expand its host range, sustained global investment in One Health governance, research, and infrastructure will be vital to prevent future pandemics and safeguard health across species.

The development of effective vaccines against emerging infectious diseases, including avian influenza strains such as H5N1 and H7N9, is hindered by the limited translational fidelity of animal models and the low throughput of traditional preclinical platforms. Human immune organoids are ex vivo, multicellular, lymphoid cultures derived from tonsil, or spleen tissue, offering a physiologically relevant and scalable system to model human germinal center biology and vaccine responses. We describe how tonsil and spleen organoids can support the rationale design of antigen and adjuvant for influenza vaccines. Coupled antigen strategies, which leverage pre-existing memory T cells, can significantly enhance responses to weak antigens, such as avian HA. Moreover, a cytokine screen performed in human immune organoids revealed distinct adjuvanticity profiles and mapped functional axes involving type I interferons and IL-12/IL-21 signaling. We propose a new paradigm: functional systems immunology, combining mechanistic perturbation in human immune organoids with high-dimensional immune profiling. This platform will enable the causal dissection of human immune regulation at a large scale. High-throughput screen of candidates will enable efficient vaccine designs.

Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) regulates NF-κB signaling and is implicated in chronic autoimmune diseases characterized by persistent inflammation. In addition to its role in restraining linear ubiquitin assembly complex-mediated linear ubiquitination of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to limit inflammasome activation, TRAF1 also stabilizes cellular inhibitor of apoptosis protein 2 (cIAP2) by protecting it from degradation. Notably, cIAP2 promotes inflammasome activation via K63-linked polyubiquitination of caspase-1. Here, we show that disrupting the TRAF1/cIAP2 interaction (V203A in humans; V196A in mice) reduces inflammasome activation. TRAF1V203A THP-1 cells exhibit diminished caspase-1 ubiquitination, leading to impaired IL-1β secretion. Similarly, TRAF1V196A mice produce significantly lower IL-1β levels after LPS challenge. In a monosodium urate crystal-induced arthritis model, TRAF1V196A mice show reduced joint inflammation, decreased synovial immune cell infiltration, and attenuated disease severity. These findings establish the TRAF1/cIAP2 axis as a key regulator of inflammasome activation and a potential therapeutic target for inflammasome-driven diseases such as gout.

Hybrid immune individuals who experience an infection after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine series show evidence of salivary anti-spike and anti-receptor binding domain (RBD) IgA antibodies with broad specificity against different variants. It is unclear how long these antibodies persist and whether they offer protection against new SARS-CoV-2 infections. We compared salivary IgA levels to full-length spike protein and its RBD of the ancestral Wuhan SARS-CoV-2 virus and the Omicron BA.1 variant in a subset of persons participating in a longitudinal study of binding antibody responses to vaccination. We assessed the decay rate of the salivary IgA antibodies in those with hybrid immunity. In our heavily vaccinated population, low levels of salivary IgA to RBD and spike was variably detected in vaccine-only immunity to both Wuhan and Omicron BA.1, but antibody levels were an order of magnitude higher in those with hybrid immunity. In hybrid immune individuals, anti-spike/RBD salivary IgA rapidly decayed over a 4-month observation period. In a multivariate analysis, salivary IgA antibody to Omicron BA.1 was not associated with protection from a new SARS-CoV-2 infection over the subsequent 10 months during the Omicron XBB.1.5, EG.5, and JN waves of infection. In contrast, receipt of a new vaccine dose was significantly associated with protection.

The ability to manipulate the mouse genome has contributed heavily to countless discoveries in biology for several decades. The Cre/loxP system enables conditional and inducible deletion of virtually any sequences in the mouse. Because Cre expression does not always predict Cre activity and does not necessarily mirror expression of the endogenous gene(s) whose cis-acting genetic elements were used to construct a given Cre "driver" mouse line, Cre "reporter" mouse lines have been developed in which expression of Cre is signified by expression of one of a variety of fluorescent or otherwise easily detectable proteins, including EYFP, tdTomato, and βgal. It is shown here that one such widely utilized Cre reporter mouse line, which expresses EYFP following Cre-mediated recombination, fails to detect a significant fraction of Cre+ T cells, as detected with an otherwise identical tdTomato-expressing Cre reporter. Given the wide use of this and similar Cre reporter mouse lines, these findings have potentially significant implications for a diverse array of studies.