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.

The CD27-CD70 pathway regulates T-cell activity either positively or negatively depending on the context of immune response. Typically, CD27 is known as a co-stimulatory receptor expressed on T cells while CD70 is the ligand expressed on antigen-presenting cells. Interestingly, CD70 is also expressed on T cells upon activation, raising an intriguing question about whether potential CD27-CD70 interaction within T cells affects T-cell response. To address this question in an antigen-specific adoptive T-cell model for tumor immunotherapy, we bred Pmel transgenic mice (JAX strain: 005023) with Cd70-/- mice to generate Pmel-Cd70-/- mice. We found that both CD27 and CD70 are expressed on Pmel T cells activated by GP100 antigen in vivo. Interestingly, T cells expressed CD27 protein at higher frequencies and higher levels in Pmel-Cd70-/- mice compared to Pmel mice with intact Cd70 gene, indicating CD27-CD70 reciprocal regulation. We inoculated Cd27-/-Cd70-/- mice with B16-F10 melanoma cells, then adoptively transferred Pmel versus Pmel-Cd70-/- T cells to compare their efficacy in controlling tumor growth. This unique system eliminates CD27-CD70-mediated interaction between host cells and adoptive T cells, allowing us to distinguish the impact of potential CD27-CD70 interaction within adoptive T cells. Our results showed that Pmel and Pmel-Cd70-/- T cells exhibited significant yet equivalent efficacy in inhibiting tumor growth, indicating that potential CD27-CD70 interaction within adoptive T cells does not affect T-cell immunotherapy in this tumor model. This work is informative for designing adoptive T-cell therapy for cancer treatment.

Natural killer (NK) cells are a key component of the innate immune system and are specialized in the recognition and elimination of virally infected, tumor, and otherwise abnormal cells. However, multiple laboratories have shown that NK cells display exquisite MHC-I-dependent memory toward haptens, complex proteins, and peptides in mice lacking RAG proteins, which are devoid of both T cells and B cells but still have intact TCR genes, in addition to abnormal NK cell expansion and activation. Here, we show that the fine antigen specificity of memory NK cells persists in the absence of functional TCR genes. The ability of NK cells to mediate adaptive responses was evaluated using contact hypersensitivity (CHS) responses to chemical haptens and peptides in TCR-β-/-δ-/- mice. Peptide specificity and memory was maintained in these mice as shown by CHS after sensitization with multiple unrelated peptides individually or as a mixture. This was done in conjunction with depletion of key immune subsets including all NK cells, Ly49C/I+ NK cells, or B cells. In the absence of NK cells, and specifically Ly49C/I+ NK cells, TCR-β-/-δ-/- mice were unable to exhibit immunological memory responses, similar to what was previously reported for Rag1-/- mice. Furthermore, depleting B cells did not impact TCR-β-/-δ-/- mice's ability to exhibit adaptive immune responses. These findings highlight and reinforce the capability of NK cells to form adaptive memory responses to peptides in the presence or absence of T cells, and without the need for functional TCR genes.

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.

The ferret is considered the "gold standard" animal model for influenza virus research. However, the mechanisms of the ferret humoral immune responses remain understudied. Here, the kinetic profile of the influenza A or B virus hemagglutinin (HA)-specific primary antibody response was tracked until the contraction phase. Additionally, the acute humoral response following a secondary infection with a homosubtypic H1N1 influenza A virus was evaluated. In particular, the HA-binding reactivity in serum was quantified and the number of HA-specific antibody-secreting cells was evaluated in different immune compartments, including peripheral blood mononuclear cells, spleen, and mediastinal lymph nodes at multiple time points postinfection. Differences in Igκ and Igλ light chain (IgL) usage within the elicited HA-specific antibody response was observed after primary and secondary influenza virus infection. Ferrets had de novo humoral immune responses that were detected approximately 7 to 10 days following influenza virus infection with an inherent Igλ serum antibody bias directed toward the HA head domain, with detectable hemagglutination inhibition activity. The Igλ bias was also extended to influenza B virus primary infections. Higher serum Igκ reactivity was detected following secondary influenza virus infection compared to the primary viral infection, which was directed toward the conserved H1 stem domain. Taken together, our findings confirm inherent IgL biases in the anti-HA antibody response expressed following influenza virus primary and secondary infections that result in a unique profile of antibody functional activity.

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.

Viral infections induce heterogeneous memory T and B cell populations that may rapidly recall and provide protection against re-infection. The immunomodulatory cytokine interleukin-10 (IL-10) is well described for its role in restricting immunopathology during viral infection; however, less is known about its role in the development of cellular and humoral immune memory. In this review, we explore the current knowledge of the role of IL-10 in the regulation of antiviral memory T and B cell development. Furthermore, we highlight the importance of the cellular source and timing of IL-10 production in regulating this complex process.

Different memory CD8+ T-cell subsets are generated following acute responses: central, effector and resident (Trm). CD8+ Trm cells established residency at the sites of infection and provide an efficient and rapid frontline defense against reinfection. The NR4A family members (NR4A1, NR4A2, and NR4A3) of orphan nuclear receptor are transiently expressed following TCR signaling and NR4As were shown to influence CD8+ T-cell response. Interestingly, Nr4a1, Nr4a2, and Nr4a3 have been reported to be transcribed by CD8+ Trm cells. NR4A1 and NR4A2 were shown to influence the generation of CD8+ Trm cells. However, evidence is still lacking for the contribution of NR4A3 during CD8+ Trm cell differentiation. In this study, we evaluated the role of NR4A3 in the differentiation and maintenance of CD8+ Trm cells. Our data demonstrate that in contrast to the other family members NR4A1 and NR4A2, NR4A3 is dispensable for the generation of CD8+ Trm cells at both epithelial and nonepithelial sites.

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.