Immunology & Cell Biology最新文献

The immune system uses a variety of DNA sensors, including endo-lysosomal Toll-like receptors 9 (TLR9) and cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). These sensors activate immune responses by inducing the production of a variety of cytokines, including type I interferons (IFN). Activation of cGAS requires DNA-cGAS interaction. Accumulation of cGAMP activates the stimulator of interferon genes (STING), ultimately leading to pathogen clearance by type I IFN production. To prevent the sensing of endogenous nuclear DNA, cGAS is usually localized in the cytoplasm. In this work, we studied the interaction and activation of cGAS by DNA containing non-CpG methyl adducts N3-methyl-C (3mC) and 7-methyl-G (7mG). We report that while DNA with 3mC and 7mG interacts with cGAS, it fails to stimulate its activity in vitro. To gain mechanistic insight, we used synthetic oligonucleotides containing 3mC and 7mG for cGAS activation. We observed that the presence of these adducts was inhibitory to cGAS-catalyzed cGAMP production and type I IFN response in human monocyte cell line THP1. Thus, our study reveals that the specific DNA base methylation adducts 3mC and 7mG contribute to the regulation of cGAS activation and provide a potential strategy for delivering DNA without activating the cGAS pathway.

A recent extensive study from the Blumenthal research group has demonstrated that Toll-like receptor 4 (TLR4) signaling from the endosomes can be uncoupled from CD14-mediated endocytosis, revealing two distinct TLR4 signaling pathways. TLR4 was the first of the toll-like receptors to be discovered and one of the most studied.

Loss of T-cell tolerance to multiple islet antigens is a key feature of autoimmune type 1 diabetes. In this study, we investigated the requirement for programmed death 1 (PD-1) expression by CD4⁺ T cells in the maintenance of self-tolerance via bystander suppression of autoreactive CD8⁺ T cells using nonobese diabetic mice. We used CRISPR/Cas9 to selectively knockout PD-1 in islet antigen-specific BDC2.5 CD4⁺ T cells and observed the impact on bystander tolerance of 8.3 CD8⁺ T cells, specific for a different islet antigen. Loss of PD-1 promoted the proliferation, Th1-like effector-memory phenotype, islet infiltration and expression of cytotoxic markers by BDC2.5 cells. PD-1-deficient BDC2.5 cells were impaired in their regulation of 8.3 cells, which proliferated more, developed an effector-memory phenotype and increased expression of effector molecules. While antigen-presenting cell maturation and migration into the pancreatic lymph node were not impacted by loss of PD-1 expression from BDC2.5 cells, migration of BDC2.5 cells out of the lymph node was required for enhanced activation of the CD8⁺ T cells. Together, these events led to accelerated diabetes progression, suggesting that PD-1 expression by CD4⁺ T cells promotes a tolerogenic microenvironment and restraining autoreactive CD8⁺ T cells.

In this article, we discuss our experiences, as medical students, in raising awareness among fellow medical students about global health issues while providing insight into how other university students sharing these interests can set up similar initiatives.

Recent advances in single-cell technologies have enabled the creation of comprehensive cell atlases, reference maps of various cell types within organisms. Here we specifically focus on T cell atlases, which offer a detailed catalog of the adaptive immune system at single-cell resolution. As such, they capture cellular diversity, functional states, and spatial dynamics across tissues, developmental stages, and disease conditions. Given the central role of T cells in orchestrating immune responses, their dysregulation underpins autoimmune disorders, cancer progression and failed immunotherapies. Therefore, a unified T cell atlas is critical for decoding such disease mechanisms, identifying therapeutic targets, and advancing personalized treatments. In this article, we explore the latest advances in T cell atlases, describing breakthroughs in multi-omics technologies, spatial profiling and computational frameworks that resolve transcriptional, epigenetic and proteomic heterogeneity. We also address persistent challenges and highlight strategies to address these gaps. Finally, we discuss emerging frontiers set to reshape our understanding of T cell dynamics in both health and diseases. Together, these insights underscore the transformative potential of T cell atlases in reconstructing precision immunology and accelerating therapeutic innovation.

Newborns represent over half of hospitalized pediatric influenza infection cases, with current influenza vaccines not effective in the first months of life. Advax^® (delta inulin) is a polysaccharide particle that targets DC-SIGN, whereas CpG55.2 is a potent murine and human toll-like receptor (TLR)-9 agonist. This study asked whether Advax or CpG alone, or combined, could enhance the protection of an inactivated influenza virus vaccine (IIV) in newborns. One-day-old mouse pups were immunized subcutaneously with a single dose of IIV alone or with Advax or Advax-CpG55.2 adjuvants and then, at 28 days of age, challenged intranasally with a lethal dose of influenza virus. While IIV alone or with CpG adjuvant provided minimal protection, Advax alone or combined with CpG55.2 induced enhanced serum anti-influenza IgM and IgG responses to IIV and protected the newborns against clinical disease. Protection induced by a single vaccine dose was highly durable and was still evident 6–9 months after a single neonatal immunization. Protection was lost in B-cell-deficient μMT pups but preserved in β2m knockout pups and in CD4⁺ and CD8⁺ T-cell-depleted pups, indicating the importance of intact humoral immunity to the enhanced protection. The neonatal benefits of Advax^® and Advax-CpG55.2 adjuvant were confirmed in newborn macaques, where they similarly enhanced serum anti-influenza antibody responses to IIV. This raises the possibility that Advax^® adjuvant alone or in combination with CpG55.2 may have utility in improving influenza vaccine protection in human newborns.

T-helper 17 (Th17) cells, a subset of CD4⁺ T cells, are key players in mucosal immunity and inflammation, distinguished by their production of IL-17 and related cytokines. In the context of cancer, Th17 cells exhibit extraordinary plasticity—adapting their phenotype and function in response to tumor microenvironmental cues. This review explores how Th17 cells mediate paradoxical roles in tumor biology, promoting either tumor progression or antitumor immunity depending on molecular context. Protumorigenic functions include fostering angiogenesis, chronic inflammation and immune evasion through IL-17-driven recruitment of neutrophils and myeloid-derived suppressor cells. Conversely, Th17 cells can transition into IFNγ-producing Th1-like cells, enhancing cytotoxic T-cell responses and tumor rejection. Key modulators of this plasticity include cytokines (IL-23, IL-12, TGF-β), hypoxia, metabolic shifts and epigenetic reprogramming. We further examine how Th17 plasticity contributes to metastasis, therapy resistance and immune modulation via interactions with tumor-associated macrophages and regulatory T cells. Finally, the review highlights emerging therapeutic strategies that target Th17 pathways through cytokine blockade, metabolic intervention, RORγ modulation and adoptive cell therapy. Understanding Th17 plasticity provides critical insights into tumor immunology and offers novel avenues for cancer immunotherapy.

In this study, we employed a coculture system to expand natural killer (NK) cells ex vivo from healthy donors and patients with breast cancer and investigated their surface marker expression. We further analyzed the activation markers of primary expanded NK cells on Day 13 using cytokine arrays and dimensionality reduction techniques. Cytokine profiles were observed on Days 0, 6 and 13 (TS-NK). To validate the anticancer activity of the expanded NK cells, we conducted lactate dehydrogenase assays against the hematologic cancer cell line K562 using cells from 10 donors (five patients with cancer and five healthy individuals). Additionally, we examined the antibody-dependent cellular cytotoxicity (ADCC) of differentiated NK cells cocultured with SK-BR-3 cells in the presence of the HER2-targeting monoclonal antibodies, trastuzumab and pertuzumab. Our findings demonstrate the stable expansion of NK cells from donor peripheral blood mononuclear cells and their potent anticancer effects and ADCC against both hematologic and solid tumors, highlighting their potential as a versatile therapeutic approach in oncology.

This Special Feature brings you the “Highlights of 2024”, a collection of short articles to bring you up to date on major advances in immunology research published in 2024. Each highlight article summarizes the key papers that drove new discoveries in a specific area of immunology. Pankhurst and Linterman¹ highlight the latest discoveries in the germinal center response and new opportunities for the development of more effective vaccines and immunotherapies. Flaman et al.² focus on key studies that provide critical insights into the development, differentiation, and longevity of antibody secreting cells in health and disease. In Lee and Reed,³ we review recent findings on age-associated B cells, the discovery of their transcriptional regulator, and the evidence for a pathogenic role in autoimmune disease. Valentini et al.⁴ discuss metabolic pathways that alter regulatory T-cell function and differentiation and their potential as therapeutic targets in inflammatory niches, tumors and autoimmune disease. McEwan et al.⁵ update us on the growing evidence that the most important risk gene for Alzheimer's disease, the apolipoprotein E variant, APOE4 drives immune dysregulation causing neuroinflammation and neurodegeneration. Eberl⁶ summarizes the role of γδ T cells in tissues during sepsis while referring to 58 Taylor Swift song titles—how many can you find? 2024 was also a big year for innate lymphoid cells (ILC), with Shen et al.⁷ discussing tissue-specific roles for ILC3, highlighting metabolic and checkpoint molecules as targets for immunotherapy. Shajan et al.⁸ summarizes the critical signaling pathways, epigenetic modifications and cytokines-regulating natural killer (NK) cell function and survival. Bourel et al.⁹ review the latest strategies to enhance NK cell cytotoxicity and memory for cell-based cancer therapy. Finally, Jose et al.¹⁰ discuss advances and clinical trials for antibody–drug conjugates, which combine monoclonal antibody specificity with cytotoxic agents to selectively deliver potent drugs to tumor cells.

Whether you are reliving some of 2024's key findings in your field or learning about the major advances in another area, this Special Feature will get you up to date and ready for another exciting year or immunology.

The author declares no conflicts of interest.

Joanne H Reed: Conceptualization; writing – original draft; writing – review and editing.

CD4⁺ T cells play a vital role in the occurrence and development of autoimmune diseases (AID). The differentiation direction and function of CD4⁺ T cells are both regulated by metabolic reprogramming, which differs across various CD4⁺ T subsets. Glutamine (Gln), as an immunoregulatory nutrient, not only provides bioenergy and biosynthesis for the differentiation and effector function of CD4⁺ T cells but also regulates intracellular redox conditions and produces metabolic intermediates that are used for epigenetic modification of effector cell genes. Here, we review the metabolic characteristics of Gln in CD4⁺ T cells and its regulatory effects on CD4⁺ T-cell differentiation and function. We also summarize potential targets on Gln metabolism for AID therapy, including Gln transporters, Gls1, GSH synthesis and epigenetic modification. However, the primary challenge remains how to achieve cell type-specific metabolic inhibition in vivo. Therefore, future research should focus on developing selective and effective therapeutic agents that modulate Gln metabolism while minimizing cytotoxicity for AID treatment.