Granulocytes, the most abundant types of leukocytes, are the first line of defense against pathogen invasion. However, the plasticity and diversity of granulocytes have been increasingly revealed, ...especially with regard to their versatile functions in orchestrating adaptive immune responses. A substantial body of recent evidence demonstrates that granulocytes can acquire the function as antigen-presenting cells under pathological or inflammatory conditions. In addition, they can acquire surface expression of MHC class II and costimulatory molecules as well as T cell stimulatory behavior when cultured with selected cytokines. The classic view of granulocytes as terminally differentiated, short-lived phagocytes is therefore changing to phenotypically and functionally heterogeneous cells that are engaged in cross-talk with other leukocyte populations and provide an additional link between innate and adaptive immunity. In this brief review, we summarize the current knowledge on the antigen-presenting capacity of granulocyte subsets (neutrophils, eosinophils, and basophils). Underlying mechanisms, relevant physiological significance and potential controversies are also discussed.
In this concise review, we summarize the concepts behind mRNA vaccination. We discuss the innate and adaptive immune response generated by mRNA vaccines in different animal models and in humans. We ...give examples of viral infections where mRNA vaccines have shown to induce potent responses and we discuss in more detail the recent SARS-CoV-2 mRNA vaccine trials in humans.
Innate immune mechanisms of mRNA vaccines Verbeke, Rein; Hogan, Michael J.; Loré, Karin ...
Immunity (Cambridge, Mass.),
11/2022, Letnik:
55, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The lipid nanoparticle (LNP)-encapsulated, nucleoside-modified mRNA platform has been used to generate safe and effective vaccines in record time against COVID-19. Here, we review the current ...understanding of the manner whereby mRNA vaccines induce innate immune activation and how this contributes to protective immunity. We discuss innate immune sensing of mRNA vaccines at the cellular and intracellular levels and consider the contribution of both the mRNA and the LNP components to their immunogenicity. A key message that is emerging from recent observations is that the LNP carrier acts as a powerful adjuvant for this novel vaccine platform. In this context, we highlight important gaps in understanding and discuss how new insight into the mechanisms underlying the effectiveness of mRNA-LNP vaccines may enable tailoring mRNA and carrier molecules to develop vaccines with greater effectiveness and milder adverse events in the future.
Lipid nanoparticle-encapsulated, nucleoside-modified mRNA vaccines produce adaptive immune responses protective against COVID-19. Here, Pardi and colleagues review the innate immune-sensing pathways of this vaccine modality and discuss research directions that may yield a next generation of mRNA vaccines with improved immunogenicity and reduced reactogenicity.
Adaptive immune responses play critical roles in viral clearance and protection against re‐infection, and SARS‐CoV‐2 is no exception. What is exceptional is the rapid characterization of the immune ...response to the virus performed by researchers during the first 20 months of the pandemic. This has given us a more detailed understanding of SARS‐CoV‐2 compared to many viruses that have been with us for a long time. Furthermore, effective COVID‐19 vaccines were developed in record time, and their rollout worldwide is already making a significant difference, although major challenges remain in terms of equal access. The pandemic has engaged scientists and the public alike, and terms such as seroprevalence, neutralizing antibodies, antibody escape and vaccine certificates have become familiar to a broad community. Here, we review key findings concerning B cell and antibody (Ab) responses to SARS‐CoV‐2, focusing on non‐severe cases and anti‐spike (S) Ab responses in particular, the latter being central to protective immunity induced by infection or vaccination. The emergence of viral variants that have acquired mutations in S acutely highlights the need for continued characterization of both emerging variants and Ab responses against these during the evolving pathogen‐immune system arms race.
Neutrophils are critical cells of the innate immune system and rapidly respond to tissue injury and infection. Increasing evidence also indicates that neutrophils have versatile functions in ...contributing to adaptive immunity by internalizing and transporting antigen and influencing antigen-specific responses. Here, we demonstrate that freshly isolated human neutrophils can function as antigen-presenting cells (APCs) to memory CD4+ T cells. Neutrophils pulsed with the cognate antigens cytomegalovirus pp65 or influenza hemagglutinin were able to present the antigens to autologous antigen-specific CD4+ T cells in a major histocompatibility complex class II (MHC-II; HLA-DR)-dependent manner. Although myeloid dendritic cells and monocytes showed superior presenting ability, neutrophils consistently displayed antigen presentation capability. Upregulation of HLA-DR on neutrophils required the presence of the antigen-specific or activated T cells whereas exposure to innate stimuli such as Toll-like receptor ligands was not sufficient. Neutrophils sorted from vaccine-draining lymph nodes from rhesus macaques also showed expression of HLA-DR and were capable of presenting vaccine antigen to autologous antigen-specific memory CD4+ T cells ex vivo. Altogether, the data demonstrate that neutrophils can adapt a function as APCs and, in combination with their abundance in the immune system, may have a significant role in regulating antigen-specific T-cell responses.
•Neutrophils can present cognate antigens to antigen-specific memory CD4+ T cells.•MHC-II and costimulatory molecules are induced on neutrophils in the presence of antigen and antigen-specific memory CD4+ T cells.
While myeloid-derived suppressor cells (MDSCs) in humans and mice have been intensively investigated, there is limited knowledge of these cells in nonhuman primates (NHPs). NHPs serve as critical ...models for late-stage testing of several biomedical inventions before proceeding with clinical trials and it is therefore important to fully understand their immune compartments and similarities with humans. Here, using antihuman cross-reactive antibodies, we provide flow cytometric analysis protocols for identification of MDSCs in the blood of rhesus macaques, one of the major NHP species as experimental models. Discrepancies and similarities between rhesus and human MDSCs are discussed.
In cancer, infection and inflammation, the immune system’s function can be dysregulated. Instead of fighting disease, immune cells may increase pathology and suppress host-protective immune ...responses. Myeloid cells show high plasticity and adapt to changing conditions and pathological challenges. Despite their relevance in disease pathophysiology, the identity, heterogeneity and biology of myeloid cells is still poorly understood. We will focus on phenotypical and functional markers of one of the key myeloid regulatory subtypes, the myeloid derived suppressor cells (MDSC), in humans, mice and non-human primates. Technical issues regarding the isolation of the cells from tissues and blood, timing and sample handling of MDSC will be detailed. Localization of MDSC in a tissue context is of crucial importance and immunohistochemistry approaches for this purpose are discussed. A minimal antibody panel for MDSC research is provided as part of the Mye-EUNITER COST action. Strategies for the identification of additional markers applying state of the art technologies such as mass cytometry will be highlighted. Such marker sets can be used to study MDSC phenotypes across tissues, diseases as well as species and will be crucial to accelerate MDSC research in health and disease.
Inducing a high magnitude of antibodies, possibly in combination with T‐cell responses that offer epitope breadth over prolonged periods of time is likely a prerequisite for effective vaccines ...against severe diseases such as HIV‐1 infection, malaria and tuberculosis. A much better understanding of the innate immune mechanisms that are critical for inducing desired responses to vaccination would help in the design of novel vaccines. The majority of human vaccines are administered into the muscle. In this brief review, we focus on the initial innate immune events that occur locally at the site of intramuscular vaccine delivery, and how they are influenced by clinically approved vaccine adjuvants. In particular, the effects on cell mobilization, cell activation and vaccine antigen uptake are reviewed. Understanding how distinct adjuvants enhance and tailor vaccine responses would facilitate the selection of the best‐suited adjuvant to improve vaccine efficacy to a given pathogen.
•TLR based adjuvants increase immunogenicity of non-live vaccines.•NHP cell subset phenotype and TLR expression reflects humans.•NHP model better translates immunogenicity of TLR adjuvants to ...clinic.•TLR adjuvants can fine tune innate immune activation.•TLR stimulation increases T and B cell magnitude and breadth in NHPs.
While transgenic mouse models are powerful for understanding how the immune system is manipulated by vaccines, they cannot fully recapitulate the characteristics of the innate immune responses leading to adaptive immunity after vaccination in humans. Outbred non-human primates are far more representative models of human vaccine responses as there is high degree of similarities in immune cell subset distributions, receptor expression (including toll-like receptors; TLRs), and immune cell functions, in addition to modeling doses and injection sites more accurately. Vaccine adjuvants targeting TLRs have shown great promise in their ability to enhance responses to non-live vaccines. As TLR ligands are molecularly defined, studies of the mechanisms by which they interact with the immune system are facilitated. In this brief review, we focus on the use of TLR3, 4, 7/8 and 9 stimulating adjuvants in NHPs by evaluating similarities between the specified TLRs in human and NHPs and highlighting recent work studying the mode of action or efficacy of TLR based adjuvants in NHPs.
Following intestinal invasion, the processes leading to systemic dissemination of the obligate intracellular protozoan Toxoplasma gondii remain poorly understood. Recently, tachyzoites representative ...of type I, II and III T. gondii populations were shown to differ with respect to their ability to transmigrate across cellular barriers. In this process of active parasite motility, type I strains exhibit a migratory capacity superior to those of the type II and type III strains. Data also suggest that tachyzoites rely on migrating dendritic cells (DC) as shuttling leukocytes to disseminate in tissue, e.g., the brain, where cysts develop. In this study, T. gondii tachyzoites sampled from the three populations were allowed to infect primary human blood DC, murine intestinal DC, or in vitro-derived DC and were compared for different phenotypic traits. All three archetypical lineages of T. gondii induced a hypermigratory phenotype in DC shortly after infection in vitro. Type II (and III) strains induced higher migratory frequency and intensity in DC than type I strains did. Additionally, adoptive transfer of infected DC favored the dissemination of type II and type III parasites over that of type I parasites in syngeneic mice. Type II parasites exhibited stronger intracellular association with both CD11c⁺ DC and other leukocytes in vivo than did type I parasites. Altogether, these findings suggest that infected DC contribute to parasite propagation in a strain type-specific manner and that the parasite genotype (type II) most frequently associated with toxoplasmosis in humans efficiently exploits DC migration for parasite dissemination.
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