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potential particle pathogen prevent prototype receptor receptor-mediated signaling recruit success trafficking tumor unpublished works vaccine formulation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.

提案摘要激发细胞毒性 CD8 T 细胞对抗细胞内病原体存在关键的疫苗障碍。疫苗技术在预防细胞内病原体感染方面取得的成功有限例如结核病、疟疾和艾滋病毒，其中 CD8 T 细胞可预防和控制感染。主要是中和或调理抗体，其功效取决于稳定的抗原谱。明矾等佐剂会引发辅助性 2 型 CD4 T 细胞，但 CD8 T 细胞免疫却很难实现。 T 细胞可以针对病原体更难突变的保守内部微生物成分。 CD8 T 细胞介导的无与伦比的效力、交叉保护性免疫和免疫记忆强调了开发 CD8 T 细胞疫苗的紧迫性为了引发 CD8 T 细胞免疫，需要佐剂。诱导树突状细胞 (DC) 呈递疫苗制剂中存在的抗原的 MHC，有效抗原呈递细胞，启动幼稚 CD8 T 细胞，MHC I 类呈递外源抗原。 DC 疫苗成分的产生是通过交叉呈现的机制进行的。因此，调节 DC 交叉呈递对于设计引发强 CD8 T 细胞免疫的佐剂至关重要。已发表和未发表的研究表明，Toll 样受体 (TLR) 可以检测微生物并发出警报免疫系统，积极调节 DC 交叉呈递在研究交叉呈递的调节时，根据内化的大小考虑抗原内化到 DC 中的途径很重要。抗原，可通过吞噬作用（对于直径 >1μm 的颗粒）或内吞作用进行内化（直径 <1μm）。我们发现 TLR 依赖性的交叉呈递调节对于内吞作用是不同的。和吞噬细胞抗原决定交叉呈递至 CD8 T 的效率。细胞是 MHC-I 分子正确的亚细胞运输至内化抗原的位点。 TLR 信号控制来自 DC 内体回收区室 (ERC) 的 MHC-I 分子的运输我们发现，特别是针对吞噬细胞抗原，例如来自细菌或受感染的垂死细胞的内吞抗原。涉及独特的 TLR 信号传导机制，控制内吞抗原交叉呈递至 CD8 T 细胞并使用 ERC 以外的细胞来源将 MHC-I 分子运输至内吞抗原。通过多种经过验证和补充的方法，我们将研究内吞的 TLR 调节机制我们将阐明抗原交叉呈递和亚细胞 MHC-I 运输到内吞抗原的过程。调节内吞抗原交叉呈递的不同 TLR 机制影响保护性循环和通过疫苗接种引发的组织驻留 CD8 T 细胞记忆我们将使用配制的原型亚单位疫苗。佐剂/TLR配体组合可参与并促进DC内吞抗原交叉呈递。破译内吞抗原交叉呈递的调节机制将直接影响针对临床相关的新旧病原体（包括具有大流行潜力的病原体）的有效 CD8 T 细胞疫苗。