Effector and Regulatory Activities of HLA-E-restricted HIV-specific abCD8 T Cells

HLA-E 限制的 HIV 特异性 abCD8 T 细胞的效应器和调节活性

基本信息

批准号：
8518235
负责人：
JUNE KAN-MITCHELL
金额：
$ 46.8万
依托单位：
UNIVERSITY OF TEXAS EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8518235
关键词：
Address Affect Affinity Antigen Presentation Autoimmunity Bacteria Binding CD8B1 gene Cell Culture Techniques Chronic Correlative Study Data Development Drug Design Epitope Mapping Epitopes Equilibrium Face Future Gagging Genetic Polymorphism HIV HIV Infections HIV vaccine HIV-1 HLA-A gene Homeostasis Human Hypersensitivity Immune Immunity In Vitro Individual Infection Inflammation Intestines KLRD1 gene Leukocytes Life Malignant Neoplasms Maps Mass Spectrum Analysis Mus Natural Killer Cells Pathology Patients Peptide Signal Sequences Peptides Population Prevention Production Proteins Proteome Protocols documentation Relative (related person)Reporting Role Specificity Structure System T-Lymphocyte Therapeutic Agents Time United Nations Vaccine Design Viral Virus Work acquired immunity allograft rejection base cost cytotoxic global health insight interest microbial new technology pathogen prevent public health relevance receptor response therapeutic vaccine therapy design vaccine development

项目摘要

DESCRIPTION (provided by applicant): HLA-E is a ubiquitously expressed non-classical class Ib molecule. Under homeostatic conditions, HLA-E preferentially presents essentially invariant signal peptides of classical class Ia proteins (HLA-A, -B, and -C) to the innate CD94/NKG2 receptors, thereby regulating NK cell activity. HLA-E-restricted regulatory CD8+ T cells may prevent autoimmunity. Of interest, with infections by certain bacteria and viruses, HLA-E displays a remarkably diverse repertoire of pathogen-derived peptides that are sensed by ¿¿ TCR of CD8+ T cells. We report the first HLA-E-restricted HIV Gag epitope (KL9) identified using in vitro-re-stimulated CD8+ T cells from an elite controller. Functional analysis f HLA-E-restricted KL9-specific T cells revealed both effector (degranulation) and regulatory functions (IL-26 production). This work will begin to dissect this yet undefined host immune immunity, particularly to map conserved epitopes and assess the character of these reactivities within the HLA-E based antigen presentation system in HIV infection. This work is important for HIV vaccine development because the virus may have co-opted this mechanism to limit host immunity. A balance between effector and regulatory immunity in the context of HLA-E might allow partial clearance of HIV, thus providing some levels of protection while avoiding excessive inflammation and pathology, albeit at the cost of viral persistence and chronic infection. Understanding how embedded HLA-E-restricted epitopes affect the induction of HIV immunity would be crucial for vaccine design. The lack of HLA-E polymorphism further implies that some HLA-E-bound epitopes may be potential candidates for a universal HIV vaccine, in contrast with those restricted by the highly polymorphic class Ia loci. Specific Aim 1 will map HLA-E-restricted epitopes in conserved domains across the HIV proteome with CD8+ T cells from elite controllers using an established protocol. Epitopes will be verified by mass spectrometry. Individual HIV epitopes are expected to elicit qualitatively distinct CD8+ responses, since the TCR-binding face of HLA-E is basically "monomorphic" and thus, the bound peptide strongly influences specificity and functions. Specific Aim 2 will examine the effector and regulatory functional profiles and public TCR usage of HLA-E-restricted CD8+ T cells to the newly mapped specificities. Three T cell cultures will be generated from elite controllers or contingently from healthy donors for each epitope mapped. Selection of public TCRs may indicate that a large segment of the human population is capable of responding and these structures can be exploited by new technologies such as TCR affinity maturation to create new classes of therapeutic agents. Specific Aim 3 will be a correlative study of HLA-E-restricted HIV-specific CD8+ T cells in 30 controllers and 40 progressor patients who are off ART. The ability of these HLA-E epitopes to interact with NKG2 receptors will also be assessed with HLA-E tetramers in 10 HIV seropositive individuals. These studies will provide insights into the role of HLA-E-restricted NK and CD8+ T cell surveillance in HIV infection.

描述（由申请人提供）： HLA-E 是一种普遍表达的非经典 Ib 类分子，在稳态条件下，HLA-E 优先呈递基本不变的经典 Ia 蛋白（HLA-A、-B 和 -C）信号肽。）对先天性 CD94/NKG2 受体的影响，调节 NK 细胞活性可能会预防自身免疫。有趣的是，在某些细菌和病毒的感染下，HLA-E 显示出极其多样化的病原体衍生肽库，这些肽可以被 ¿ ¿ CD8+ T 细胞的 TCR。我们报告了使用来自精英控制器的体外重新刺激的 CD8+ T 细胞对 HLA-E 限制性 KL9 特异性 T 细胞进行功能分析鉴定的第一个 HLA-E 限制性 HIV Gag 表位 (KL9)。揭示了效应子（脱颗粒）和调节功能（IL-26 的产生）。这项工作将开始剖析这种尚未定义的宿主免疫免疫，特别是绘制保守表位图并评估其免疫功能。 HIV 感染中基于 HLA-E 的抗原呈递系统内这些反应的特征对于 HIV 疫苗的开发很重要，因为病毒可能已经选择了这种机制来限制宿主免疫之间的效应和调节免疫之间的平衡。 HLA-E 可能允许部分清除 HIV，从而提供一定程度的保护，同时避免过度炎症和病理，但代价是病毒持续存在和慢性感染。了解嵌入的 HLA-E 限制性表位如何影响 HIV 免疫的诱导。对于疫苗设计至关重要。 HLA-E 多态性的缺乏进一步意味着一些 HLA-E 结合表位可能是通用 HIV 疫苗的潜在候选表位，与高度多态性 Ia 类基因座限制的表位相反，特定目标 1 将映射 HLA-E 限制性表位。使用既定方案，使用来自精英控制者的 CD8+ T 细胞对 HIV 蛋白质组中的保守结构域中的表位进行质谱分析，预计将得出质量上不同的表位。 CD8+ 反应，因为 HLA-E 的 TCR 结合面基本上是“单态的”，因此结合的肽强烈影响特异性和功能。具体目标 2 将检查 HLA-E 的效应器和调节功能特征以及公共 TCR 用途。将 CD8+ T 细胞限制为新绘制的特异性，将从精英控制者或偶然从健康捐赠者中产生三种 T 细胞培养物。表位映射的选择可能表明大部分人群能够做出反应，并且这些结构可以通过 TCR 亲和力成熟等新技术来利用，以创建新类别的治疗剂。对 30 名控制者和 40 名停止接受 ART 的进展患者进行 HLA-E 限制性 HIV 特异性 CD8+ T 细胞研究，了解这些 HLA-E 表位与相互作用的能力。还将在 10 名 HIV 血清阳性个体中使用 HLA-E 四聚体评估 NKG2 受体，这些研究将深入了解 HLA-E 限制性 NK 和 CD8+ T 细胞监测在 HIV 感染中的作用。