Harnessing Tissue Resident Memory T Cells for Immunotherapy of Herpes Virus Infections

利用组织驻留记忆 T 细胞进行疱疹病毒感染的免疫治疗

基本信息

批准号：
10160756
负责人：
Lawrence Corey
金额：
$ 56.49万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-13 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160756
关键词：
Anatomy Antigenic Specificity Antigens Antiviral Agents Area Autologous Bar Codes Binding Sites Biopsy CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Cervical Cervix Uteri Characteristics Chronic Communicable Diseases Data Dermal Detection Emulsions Genetic Transcription Genital Genitalia Genome Genotype Herpes Simplex Virus Vaccines Herpesviridae Herpesvirus 1 Human Herpesvirus 2 Immune response Immune system Immunization Immunologic Surveillance Immunotherapeutic agent Immunotherapy Lasers Length Lesion Memory Methods Modeling Mucous Membrane Natural History Neurites Pattern Peripheral Blood Mononuclear Cell Persons Phenotype Population Proteins RNA Reporter Sampling Sequence Homology Simplexvirus Site Skin Skin Tissue Specificity System T memory cell T-Cell Receptor T-Lymphocyte Technology Time Tissues Vaccination Vaccine Design Vaccines Viral Virion Virus Diseases Vulva Work afferent nerve base complementarity-determining region 3 cytokine deep sequencing design first responder healing novel novel strategies reproductive tract seropositive single cell sequencing synthetic biology tool vaccine evaluation

项目摘要

PROJECT SUMMARY Recent work has shown that tissue resident memory (TRM) CD8+ T cells are the first line of defense for containing reactivated HSV-2 in genital skin. Deep sequencing of these unique cells has shown their TCRs differ from the TCRs detected in PBMC of the same person sampled over time, suggesting they may be directed to as yet unidentified HSV-2 antigens. As all current immunotherapeutic vaccines for HSV-2 are designed based upon antigens derived from PBMC, defining the antigenic targets of TRM cells may enhance the efficacy of novel immunotherapeutic approaches to HSV. We have recently identified TCRs of the α and β chain of laser capture purified TRM from genital skin biopsies and utilized synthetic biology to create autologous TCRs, and shown that some of these resident CD8+ T cells found in genital skin are HSV-2 specific and are directed at targets not currently emphasized in immunotherapeutic approaches to HSV-2. This proposal utilizes single cell emulsion based bar coding technology to identify in a high-throughput unbiased approach full-length TCR α and β chains of CD8+ and CD4+ T cells with RNA/protein signatures of TRM cells in cervical and vulvar tissue, as well as PBMCs of HSV-2 infected persons. We will use synthetic biology to create “reporter” T cells that can then be evaluated for their HSV specificity using a novel HSV-1/HSV-2 vireome. Identification of these cognate antigens of the TRM population is likely to yield new approaches for vaccine design.

项目概要最近的研究表明，组织驻留记忆 (TRM) CD8+ T 细胞是生殖器皮肤中含有重新激活的 HSV-2，对这些独特细胞的深度测序显示了它们的 TCR。与同一个人随时间采样的 PBMC 中检测到的 TCR 不同，表明它们可能是目前所有针对 HSV-2 的免疫治疗疫苗都是针对尚未鉴定的 HSV-2 抗原。基于来自 PBMC 的抗原设计，定义 TRM 细胞的抗原靶点可能会增强我们最近鉴定了 α 和 β 的 TCR。激光捕获链从生殖器皮肤活检中纯化 TRM，并利用合成生物学创建自体 TRM TCR，并表明在生殖器皮肤中发现的一些常驻 CD8+ T 细胞是 HSV-2 特异性的，并且是该提案利用了目前 HSV-2 免疫治疗方法中未强调的目标。基于单细胞乳液的条形码技术，以高通量、公正的方法识别全长 CD8+ 和 CD4+ T 细胞的 TCR α 和 β 链以及宫颈和外阴 TRM 细胞的 RNA/蛋白质特征我们将使用合成生物学来创建“报告”T 细胞。然后可以使用新的 HSV-1/HSV-2 病毒体鉴定来评估其 HSV 特异性。 TRM 群体的同源抗原可能会产生疫苗设计的新方法。