Immunology & Cell Biology最新文献

This study assessed how the interaction between human monocyte dectin-1 and β-glucan induces CD83 expression using THP-1 cells as a model. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to assess the dynamics of membrane-bound CD83 (mCD83) and soluble CD83 (sCD83) expression. Insoluble β-glucan induced CD83 expression more effectively than that of soluble β-glucan. Additionally, our findings indicate that the activation of nuclear factor-kappa B (NFκB) and nuclear factor of activated T cells (NFAT) plays a crucial role in the dectin-1 signaling pathway. sCD83 production is driven by metalloproteinases following mCD83 expression and inhibits mCD83 expression. This study offers novel insights into the immunoregulatory role of CD83 and its regulatory mechanisms, highlighting potential strategies for treating fungal infections and autoimmune diseases.

Immunology & Cell Biology 2025; 103: 820; https://doi.org/10.1111/imcb.70055

Correction to: Immunology & Cell Biology 2025; 103: 192−212. https://doi.org/10.1111/imcb.12848

We made an error in providing the grant number in the acknowledgement section. The current reference to the grant, “This work was supported by the NIH Office of the Director award R01-AI 146581 to Jayajit Das” should be changed to “This work was supported by the NIH Office of the Director award R01-AI143740 to Jayajit Das.”

We apologize for this error.

Multiple sclerosis is a complex neurological disorder, involving both the adaptive and innate immune systems as well as the CNS. The interaction between these systems is complex, and as such, there is the potential for MS therapies to have conflicting effects in different tissues. It is therefore critical that in addition to tissue-specific studies, system-wide effects of potential therapeutic pathways are explored. The circulating protein Gas6 is a promising therapy to promote remyelination in people with multiple sclerosis. Gas6 is a ligand for the TAM family of receptor protein tyrosine kinases that are widely expressed in the immune system and in the CNS, highlighting the potential for multi-system effects as a result of Gas6 treatment. In this study, we demonstrate that global genetic deletion of either Gas6 or the Gas6 receptor Tyro3 results in reduced disease severity following induction of experimental immune encephalomyelitis in mice. The reduction in severity was accompanied by increased expression of both IL-4 and IL-17A in Tyro3 KO mice lymph node tissue and decreased expression of both cytokines in spinal cord tissues. IL-4 is a cytokine known to be protective in inflammatory demyelination in mice. Conversely, the cytokine IL-17A is known to be pathological. The overall shift to reduced disease severity highlights the multi-faceted role of TAM receptor signaling in inflammatory demyelination.

T follicular helper (T_FH) cells are a helper T-cell subset that is defined by their localisation to B-cell areas of secondary lymphoid tissues, enabling them to provide their B-cell helper function. Precursors of T_FH cells migrate to the B-cell follicles by upregulating CXCR5 and downregulating CCR7, a process that can be blocked by S1PR1 overexpression. T_FH cells and their precursors also express the early activation antigen CD69, which is a negative regulator of S1PR1. In this study, we tested the hypothesis that CD69 expression by T_FH cells is important for their differentiation and localisation after immunization. Genetic deletion of CD69 on T_FH cells and a proportion of their precursors did not alter their formation, nor their ability to support high-affinity B-cell responses. This demonstrates that although CD69 is expressed highly on T_FH cells, it is not necessary for their formation or their B-cell helper functions in lymph nodes (LNs).

Tumor rejection is primarily mediated by cytotoxic T cells, making them critical targets for therapeutic cancer vaccines. Vaccine adjuvants can modulate innate immunity, influencing adaptive immune responses. For particulate adjuvants, such as polymeric nanoparticles, physicochemical properties—including size, charge, composition and antigen location within the formulation—can shape these responses. Free-soluble antigens typically fail to induce sufficient dendritic cell maturation and cross-presentation needed for robust CD8⁺ T-cell activation. However, this can be enhanced by delivering antigen with nanoparticles of appropriate size. While adjuvants like oil-in-water emulsions do not require antigen association for vaccine efficacy, the importance of antigen location in the adjuvanticity of polymeric nanoparticles is less clear. We demonstrate that colocalization of antigen and polymeric nanoparticles through antigen adsorption enhances proliferation and activation of antigen-specific CD8⁺ T cells following intramuscular vaccination. While type 1 conventional dendritic cells (cDC1) can prime CD8⁺ T cells in other settings, their requirement with polymeric nanoparticles has not been fully addressed. We show that nanoparticle-induced CD8⁺ T-cell responses rely on cDC1s. The therapeutic efficacy of a polymeric nanoparticle vaccine was significantly enhanced when antigen was adsorbed on nanoparticles, leading to reduced tumor growth and prolonged survival in mice challenged with immunologically hot (MC38) and cold (B16F10) tumors expressing ovalbumin. Furthermore, vaccination with nanoparticle-adsorbed antigen synergized with anti-PD-1 checkpoint blockade, enhancing protection, especially against B16F10-ovalbumin tumors. This work highlights the role of antigen association with polymeric nanoparticles in eliciting CD8⁺ T-cell responses for the development of effective therapeutic cancer vaccines.

Advax^® is a delta inulin polysaccharide adjuvant shown in animal models to enhance and accelerate influenza vaccine protection. A clinical trial was conducted in 109 healthy adult participants aged 18–70 years randomized to receive a single intramuscular seasonal trivalent influenza vaccine (TIV) alone or formulated with 5 or 10 mg Advax^® adjuvant to explore the effect of the adjuvant on the humoral immune response. The addition of Advax^® 10 mg to TIV accelerated the rise in serum influenza-specific antibodies, with this group exhibiting significantly higher increases in hemagglutinin inhibition (HAI) against 3 of the 3 vaccine serotypes at 7 days post-vaccination (7 dpv), 2 at 14 dpv and 1 at 21 dpv. By 7 dpv, the Advax 10-mg group achieved HAI seroprotection rates of 96.9% against H1N1, 100% against H3N2 and 46.9% against influenza B versus rates of 86.1%, 100% and 22.2%, respectively, for the TIV alone group. The Advax^®-adjuvanted groups demonstrated an increased frequency of non-silent CDR3 mutations in the B cell receptor heavy chain of peripheral blood IgG⁺ and IgM⁺ plasmablasts at 7 dpv, consistent with the adjuvant enhancing B cell affinity maturation in IgM⁺ and IgG⁺ plasmablasts independently of class switch recombination. The ability of Advax adjuvant to accelerate humoral responses against influenza could be advantageous during influenza outbreaks when time to protection is of the essence. Further studies are needed into the mechanisms whereby delta inulin accelerates vaccine immunity.

CD4⁺ tissue-resident memory T (T_RM) cells are essential for immune protection in the lungs, providing rapid responses against respiratory pathogens. Unlike circulating memory T cells, CD4⁺ T_RM cells persist in the tissue parenchyma and possibly inducible lymphoid tissues, where they facilitate pathogen clearance through cytokine production and interactions with local immune cells. While CD8⁺ T_RM cells are well studied, the role of CD4⁺ T_RM cells in immunity remains less defined and is the focus of this review. Distinct subsets, based on the effector T_H1, T_H2, T_H17 and T follicular helper (T_FH)-like tissue-resident helper (T_RH) cells, contribute to antiviral, antibacterial, antifungal and vaccine-induced immunity. CD4⁺ T_RM cells play a key role in infections, enhancing immune responses and supporting antibody production. However, they are also implicated in chronic inflammation, allergies and fibrosis. Given their importance, vaccines aiming to elicit lung-resident CD4⁺ T_RM cells, particularly via mucosal delivery, have shown promise in inducing long-term protective immunity. Intranasal vaccination strategies, such as live-attenuated influenza virus and tuberculosis vaccines, have successfully generated CD4⁺ T_RM cells, highlighting their potential for respiratory pathogen control. In this review, we focus on CD4⁺ T_RM cells, their differentiation, maintenance and role, especially in the lungs.

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.