MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE304585 | GEO | 2025/08/29
REPOSITORIES: GEO
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Project description:Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses, with reactogenicity influencing their use during and beyond the COVID-19 pandemic. However, despite the clinical significance, the underpinning mechanisms remain unclear. Innate and innate-like lymphocytes, such as mucosal-associated invariant T cells, are highly sensitive to cytokines and can enhance both innate and adaptive vaccine responses. We compared longitudinal human immune responses and reactogenicity following homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination to define the interactions between innate-like lymphocytes and adaptive immunity – and their in vivo consequences. Specifically, Ad vector priming elicited robust early type I interferon (IFN)-mediated activation of innate-like T cells, augmenting T cell responses (innate to adaptive signalling), which diminished upon boosting in the presence of anti-vector immunity. In contrast, mRNA vaccine responses in innate-like cells were markedly enhanced after boosting. This was initiated by IFN-γ signalling from spike-specific memory T cells and amplified by IFN-γR+ innate-like lymphocyte networks (adaptive to innate signalling). Importantly, extending the interval between doses reduced inflammatory responses to mRNA vaccination. In an independent clinical trial, spike-specific T cells predicted severe reactogenicity to mRNA vaccine boosting regardless of the dosing interval and vaccine type. These findings reveal a close integration of innate-like and adaptive responses to novel vaccines, including an IFN-γ-mediated function of innate-like T cells in orchestrating critical early responses to mRNA vaccines which may have significant implications for optimising future vaccine regimens.
2025-08-29 | GSE304584 | GEO
Project description:Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses, with reactogenicity influencing their use during and beyond the COVID-19 pandemic. However, despite the clinical significance, the underpinning mechanisms remain unclear. Innate and innate-like lymphocytes, such as mucosal-associated invariant T cells, are highly sensitive to cytokines and can enhance both innate and adaptive vaccine responses. We compared longitudinal human immune responses and reactogenicity following homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination to define the interactions between innate-like lymphocytes and adaptive immunity – and their in vivo consequences. Specifically, Ad vector priming elicited robust early type I interferon (IFN)-mediated activation of innate-like T cells, augmenting T cell responses (innate to adaptive signalling), which diminished upon boosting in the presence of anti-vector immunity. In contrast, mRNA vaccine responses in innate-like cells were markedly enhanced after boosting. This was initiated by IFN-γ signalling from spike-specific memory T cells and amplified by IFN-γR+ innate-like lymphocyte networks (adaptive to innate signalling). Importantly, extending the interval between doses reduced inflammatory responses to mRNA vaccination. In an independent clinical trial, spike-specific T cells predicted severe reactogenicity to mRNA vaccine boosting regardless of the dosing interval and vaccine type. These findings reveal a close integration of innate-like and adaptive responses to novel vaccines, including an IFN-γ-mediated function of innate-like T cells in orchestrating critical early responses to mRNA vaccines which may have significant implications for optimising future vaccine regimens.
2025-08-29 | GSE304583 | GEO
Project description:MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines [MAIT]
| PRJNA1301834 | ENA
Project description:MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines
| PRJNA1301826 | ENA
Project description:MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines [tempus]
| PRJNA1301831 | ENA
Project description:Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we show that peritumoral injection of in vivo-expanded MAIT cells into RAG1-/- mice with MC38-derived tumors inhibits tumor growth compared to control. Multiplex cytokine analyses show that tumors from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting an association between eosinophil recruitment and tumor inhibition. In a human peripheral leukocyte co-culture model, we show that leukocytes stimulated with MAIT ligand show an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we show that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy.
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Project description:Two HPV virus-like particle (VLP) vaccines, HPV-16/18 (GlaxoSmithKline, Cervarix®) and HPV-6/11/16/18 (Merck, Gardasil®), are currently licensed in the United States. Given the similar antigenic content but different adjuvant formulations in the 2 vaccines, they provide an efficient method for evaluating adjuvants and comparing the kinetics of the innate and adaptive immune responses. We randomized women to receive either Cervarix® or Gardasil®, followed 6 month vaccination delivery schedules per manufacturer's recommendations, and analyzed the humoral immune response, T cell response, and circulating plasma cytokine levels in response to vaccination. Cervarix® recipients had higher anti-HPV-16 antibody and neutralization titers at month 7, and elevated anti-HPV-18 antibody and neutralization titers at months 7 and 12. Antibody avidity was similar for the 2 vaccines. HPV-31 was the only phylogenetically related non-vaccine HPV type, for which there is evidence of cross-protection, to be cross-neutralized and only in response to Cervarix®. Comparing CD4+ T cell cytokine responses at month 12, there was a trend of increased levels of IL-2 and TNF-α in the Cervarix® groups versus the Gardasil® groups that was consistent across all 4 tested HPV types (16/18/33/45). Elevated levels of circulating plasma cytokine/chemokines were observed post first vaccination in Gardasil® recipients and proinflammatory cytokines were elevated following 1st and 3rd Cervarix® vaccinations. Cervarix® and Gardasil® are both highly immunogenic vaccines. Higher antibody levels and CD4 T cell responses were achieved with Cervarix® after 3 doses, although similar affinity maturation was measured for the 2 vaccines. The clinical implications of the differences in immune responses are unknown.
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Project description:Hepatitis C virus (HCV) remains a public health problem of global importance, even in the era of potent directly-acting antiviral drugs. In this chapter, I discuss immune responses to acute and chronic HCV infection. The outcome of HCV infection is influenced by viral strategies that limit or delay the initiation of innate antiviral responses. This delay may enable HCV to establish widespread infection long before the host mounts effective T and B cell responses. HCV's genetic agility, resulting from its high rate of replication and its error prone replication mechanism, enables it to evade immune recognition. Adaptive immune responses fail to keep up with changing viral epitopes. Neutralizing antibody epitopes may be hidden by decoy structures, glycans, and lipoproteins. T cell responses fail due to changing epitope sequences and due to exhaustion, a phenomenon that may have evolved to limit immune-mediated pathology. Despite these difficulties, innate and adaptive immune mechanisms do impact HCV replication. Immune-mediated clearance of infection is possible, occurring in 20-50% of people who contract the disease. New developments raise hopes for effective immunological interventions to prevent or treat HCV infection.
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Project description:Endothelial cells (ECs) act as gatekeepers and signalling hubs that coordinate communication between blood vessels and surrounding tissues by regulating vascular tone, immune responses and numerous other physiological processes. During vascular inflammation commonly associated with aging, atherosclerosis, diabetes and autoimmunity, a range of biological, environmental and physical stressors can induce activation and apoptosis of ECs. Apoptotic bodies (ApoBDs) are large (~1–5 μm), membrane‑bound extracellular vesicles generated solely through apoptotic cell disassembly, that are increasingly recognised as mediators of intercellular communication via the transfer of bioactive molecules to target cells. Although EC apoptosis is a central feature of vascular inflammatory disorders, the formation of EC‑derived ApoBDs and their immunomodulatory roles when formed in an inflammatory environment, remains poorly defined. This study aimed to characterise the functional properties of EC‑derived ApoBDs generated under inflammatory conditions in vitro. A proteomics analysis of EC‑derived ApoBDs revealed that EC‑ApoBDs generated during inflammation (‘iApoBDs’) were enriched in inflammatory cytokines/chemokines, adhesion molecules and antigen presentation machinery compared with non inflammatory (‘ApoBD’) controls. Functionally, iApoBDs promoted monocyte chemotaxis via the release of MCP-1, while altered expression of the adhesion molecule ICAM 1 enhanced efferocytosis by macrophages in vitro and in vivo. Furthermore, iApoBDs generated from antigen pulsed HUVECs promoted IFN‑𝛾 expression by peptide specific CD8+ T cells in an in vitro model of antigen presentation. These findings demonstrate that within an inflammatory setting, apoptotic ECs can participate in continued communication with their environment via the generation of ApoBDs, thereby modulating innate and adaptive immune processes. The formation of ApoBDs by ECs may serve as a target for therapeutic interventions in inflammatory vascular diseases.
2025-10-20 | PXD067178 | Pride
Project description:The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus erythematosus (SLE) through its role in neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, and organ damage. The role of this enzyme in mouse models of autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4-KO models have given conflicting results. The role of PAD2 in SLE has not been investigated. The differential roles of PAD2 and PAD4 in TLR-7-dependent lupus autoimmunity were examined. Padi4-/- displayed decreased autoantibodies, type I IFN responses, immune cell activation, vascular dysfunction, and NET immunogenicity. Padi2-/- mice showed abrogation of Th subset polarization, with some disease manifestations reduced compared with WT but to a lesser extent than Padi4-/- mice. RNA sequencing analysis revealed distinct modulation of immune-related pathways in PAD-KO lymphoid organs. Human T cells express both PADs and, when exposed to either PAD2 or PAD4 inhibitors, displayed abrogation of Th1 polarization. These results suggest that targeting PAD2 and/or PAD4 activity modulates dysregulated TLR-7-dependent immune responses in lupus through differential effects of innate and adaptive immunity. Compounds that target PADs may have potential therapeutic roles in T cell-mediated diseases.
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