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Toll-like receptor control of endocytic antigen cross-presentation

Toll 样受体控制内吞抗原交叉呈递

基本信息

批准号：
10735354
负责人：
Julie Magarian Blander
金额：
$ 67.56万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735354
关键词：
Adjuvant Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Bacteria Binding CD14 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell membrane Cells Cellular Immunity Cellular biology Clinical Cross Presentation Cytoplasmic Tail Dendritic Cells Dengue Virus Development Diameter Ebola virus Endocytosis Endosomes HIV Hepatitis A Hepatitis B Human Papilloma Virus Vaccine ITAM Immune system Immunity Immunologic Memory Infection Infection Control Inflammatory Response Influenza Influenza A virus Licensing Ligands Liposomes MHC Class I Genes Major Histocompatibility Complex Malaria Mediating Membrane Memory Meningococcal vaccine Microbe Mus Mutate Nature Nucleoproteins PIK3CG gene Particulate Pathway interactions Peptides Pertussis Phagocytes Phagocytosis Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Play Pneumococcal vaccine Process Proteins Publishing QS21 Receptor Cell Receptor Signaling Recombinant Proteins Recycling Regulation Role Route Saponins Signal Transduction Site Source Subunit Vaccines T cell response T memory cell TLR2 gene Technology Tissues Toll-like receptors Tuberculosis Vaccinated Vaccination Vaccine Antigen Vaccines Vesicle Viral Virus Virus-like particle aluminum sulfate clinically relevant cytotoxic CD8 T cells design emerging pathogen in vivo microbial microorganism antigen nanoparticle novel pandemic influenza pandemic potential particle pathogen prevent prototype receptor receptor-mediated signaling recruit success trafficking tumor unpublished works vaccine formulation

项目摘要

PROPOSAL SUMMARY There are critical vaccine barriers to eliciting cytotoxic CD8 T cells against intracellular pathogens. Current vaccine technologies have yielded limited success for protection against infections with intracellular pathogens like tuberculosis, malaria, and HIV where CD8 T cells prevent and control infection. Licensed vaccines generate mostly neutralizing or opsonizing antibodies, and their efficacy is contingent on a stable antigenic profile. Some adjuvants like alum elicit helper type 2 CD4 T cells, but CD8 T cell immunity has been difficult to achieve. CD8 T cells can target conserved internal microbial components that are more difficult for pathogens to mutate. The unparalleled potency, cross-protective immunity, and immunological memory mediated by CD8 T cells underscores the urgency of developing CD8 T cell vaccines. To elicit CD8 T cell immunity, an adjuvant needs to induce MHC presentation of the antigens present in the vaccine formulation by dendritic cells (DC), potent antigen-presenting cells that prime naïve CD8 T cells. The MHC class I presentation of exogenous antigens such as vaccine components by DC takes place through cross-presentation. Understanding the mechanisms that regulate DC cross-presentation is thus critical for designing adjuvants that elicit strong CD8 T cell immunity. Our published and unpublished work has shown that Toll-like receptors (TLR), which detect microbes and alert the immune system, positively regulate DC cross-presentation. When studying the regulation of cross-presentation, it is important to consider the route of antigen internalization into DC. Depending on the size of the internalized antigen, internalization can be through phagocytosis (for particles that are >1µm in diameter) or endocytosis (<1µm in diameter). We found that the TLR-dependent regulation of cross-presentation is different for endocytic and phagocytic antigens. The common component that dictates the efficiency of cross-presentation to CD8 T cells is correct subcellular trafficking of MHC-I molecules to sites of internalized antigen. For phagocytic antigens, TLR signals control the traffic of MHC-I molecules from endosomal recycling compartments (ERC) in DC specifically to phagocytic antigens such as from bacteria or infected dying cells. For endocytic antigens, we found that a distinct TLR signaling machinery is involved, which controls endocytic antigen cross-presentation to CD8 T cells and traffics MHC-I molecules to endocytosed antigen from a cellular source other than the ERC. Using a variety of validated and complementary approaches, we will investigate TLR-regulated mechanisms of endocytic antigen cross-presentation and subcellular MHC-I trafficking to endocytosed antigens. We will elucidate how the distinct TLR mechanisms that regulate endocytic antigen cross-presentation impact protective circulating and tissue-resident CD8 T cell memory elicited by vaccination. We will use prototype subunit vaccines formulated with adjuvant/TLR ligand combinations that engage and boost DC endocytic antigen cross-presentation. Deciphering regulatory mechanisms of endocytic antigen cross-presentation will directly impact the design of effective CD8 T cell vaccines to clinically relevant old and new pathogens including those with pandemic potential.

提案摘要存在关键的疫苗屏障来引发针对细胞内病原体的细胞毒性CD 8 T细胞。电流疫苗技术在防止细胞内病原体感染方面取得的成功有限如结核病、疟疾和艾滋病，其中CD 8 T细胞预防和控制感染。许可疫苗产生大多数是中和或调理抗体，并且它们的效力取决于稳定的抗原谱。一些佐剂如明矾可诱导辅助2型CD 4 T细胞，但CD 8 T细胞免疫难以实现。CD8 T细胞可以靶向保守的内部微生物成分，这些成分对病原体来说更难突变。的无与伦比的效力、交叉保护性免疫和由CD 8 T细胞介导的免疫记忆强调了开发CD 8 T细胞疫苗的紧迫性。为了引发CD 8 T细胞免疫，佐剂需要通过树突状细胞（DC）诱导疫苗制剂中存在的抗原的MHC呈递，抗原提呈细胞，引发幼稚的CD 8 T细胞。MHC I类分子呈递外源性抗原，因为DC通过交叉呈递发生疫苗组分。了解这些机制，因此，调节DC交叉递呈对于设计引发强CD 8 T细胞免疫的佐剂至关重要。我们已发表和未发表的工作表明，Toll样受体（TLR），检测微生物和警报，免疫系统，积极调节DC交叉呈递。在研究交叉呈递的调节时，重要的是考虑抗原内化到DC中的途径。取决于内部化的抗原，内化可以通过吞噬作用（对于直径>1µm的颗粒）或内吞作用（直径<1µm）。我们发现TLR依赖的交叉呈递调节与内吞作用不同，和吞噬细胞抗原。决定CD 8 T交叉呈递效率的共同成分细胞是正确的亚细胞运输MHC-I分子的网站内化抗原。对于吞噬抗原， TLR信号控制DC中MHC-I分子从内体再循环隔室（ERC）的运输特异性地针对吞噬抗原，例如来自细菌或感染的垂死细胞的吞噬抗原。对于内吞抗原，我们发现一个独特的TLR信号机制参与其中，它控制内吞抗原交叉呈递给CD 8 T细胞并将MHC-I分子从ERC以外的细胞来源运输至内吞抗原。使用各种验证和补充的方法，我们将研究TLR调节的内吞机制，抗原交叉呈递和亚细胞MHC-I向内吞抗原的运输。我们将阐明调节内吞抗原交叉呈递的不同TLR机制影响保护性循环，免疫接种引起的组织驻留CD 8 T细胞记忆。我们将使用亚单位疫苗的原型与佐剂/TLR配体组合，其参与并促进DC内吞抗原交叉呈递。解读内吞抗原交叉呈递的调节机制将直接影响免疫调节剂的设计。有效的CD 8 T细胞疫苗用于临床相关的旧的和新的病原体，包括具有大流行潜力的病原体。