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

• 批准号: 8408888
• 负责人: JUNE KAN-MITCHELL
• 金额: $ 53.16万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 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/8408888
• 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; receptor; response; therapeutic vaccine; therapy design; vaccine development

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. PUBLIC HEALTH RELEVANCE: The United Nations estimated in 2009 that 33 million people worldwide were living with HIV-1 Infection with 2.6 million new infections (http://www.unaids.org/globalreport/documents/20101123_GlobalReport_full_en.pdf). Development of preventative and therapeutic vaccines is crucial to address this significant global health problem. Optimal vaccine development requires insight into the mechanisms of protective responses to HIV. This proposal will study a recently identified new subset of white blood cells (CD8+ T cells) that can affect both spontaneous and acquired immunity to HIV.

描述（由适用提供）：HLA-E是一种普遍表达的非古典IB分子。在体内稳态条件下，HLA -E优先呈现经典IA类蛋白（HLA -A，-b和-c）的不变信号宠物，以便于先天的CD94/NKG2受体，从而调节NK细胞活性。 HLA-E限制的调节CD8+ T细胞可能会防止自身免疫性。感兴趣的是，HLA-E带有某些细菌和病毒的感染，显示了由CD8+ T细胞的TCR感测的病原体衍生肽的明显潜水曲目。我们报告了使用精英控制器的体外刺激的CD8+ T细胞鉴定出的第一个HLA-E限制的HIV GAG表位（KL9）。功能分析F HLA-E限制的KL9特异性T细胞揭示了效应子（脱粒）和调节功能（IL-26产生）。这项工作将开始剖析这种但不确定的宿主免疫免疫，特别是为了绘制配置的表位并评估HIV感染中基于HLA-E的抗原表现系统中这些反应率的特征。这项工作对于HIV疫苗的发育很重要，因为该病毒可能已经采用了这种机制来限制宿主免疫组织化学。在HLA-E背景下，效应子和调节性免疫组织化学之间的平衡可能允许部分清除HIV，从而提供一定程度的保护，同时避免过多的感染和病理学，尽管以病毒持久性和慢性感染为代价。了解嵌入的HLA-E限制表位如何影响HIV免疫的诱导对于疫苗设计至关重要。缺乏HLA-E多态性进一步意味着某些HLA-E结合的表位可能是通用HIV疫苗的潜在候选者，而受到高度多态型IA基因座的限制的表位。特定的目标1将使用已建立的方案与精英控制器的CD8+ T细胞一起绘制跨HIV蛋白质组构成的域中的HLA-E限制表位。表位将通过质谱验证。由于HLA-E的TCR结合面基本上是“单态”，因此单个HIV表位有望在质量上不同的CD8+反应上引起差异性不同，因此结合的肽强烈影响特异性和功能。具体目标2将检查效应子和调节功能曲线以及HLA-E限制的CD8+ T细胞的公共TCR使用对新映射的规格。每个T细胞培养物将是由精英控制器或每个健康捐赠者的三个T细胞培养物生成的 映射的表位。公共TCR的选择可能表明大部分人口能够做出响应，这些结构可以通过TCR亲和力成熟等新技术来探索，以创建新的治疗剂。特定的目标3将是对30个控制器中HLA-E限制的HIV特异性CD8+ T细胞的相关研究，而40名不使用ART的进步者患者。这些HLA-E表位与NKG2受体相互作用的能力也将与HLA-E四聚体在10个HIV血清阳性个体中进行评估。这些研究将提供有关HLA-E限制性NK和CD8+ T细胞监测在HIV感染中的作用的见解。 公共卫生相关性：联合国估计，2009年估计，全球3,300万人患有HIV-1感染，有260万新的感染（http://wwwww.unaids.org/globalreport/documents/20101123_globalreport_globalreport_full_en.pdf）。预防和治疗疫苗的开发对于解决这一重大的全球健康问题至关重要。最佳疫苗开发需要深入了解艾滋病毒保护性反应的机制。该建议将研究最近确定的白细胞（CD8+ T细胞）的新子集，该子集可能影响艾滋病毒的赞成和获得的免疫学。