Molecular Mechanisms of MHCII Recognition by CD8 T Cells in HIV Non-Progressor Patients

HIV非进展患者CD8 T细胞识别MHCII的分子机制

• 批准号: 9241343
• 负责人: JOHN W KAPPLER
• 金额: $ 27.74万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241343
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Alleles; Antigen-Presenting Cells; Antigens; Antiviral Agents; Binding; Biochemical; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clone Cells; Collaborations; Complex; Crystallization; Cytomegalovirus; Docking; Epitopes; Flow Cytometry; Frequencies; Goals; HIV; HIV Infections; HIV Nonprogressors; HIV Seropositivity; HIV vaccine; HLA-B Antigens; HLA-DR Antigens; HLA-DR1 Antigen; HLA-DRB1; Histocompatibility Antigens Class II; Human; Immune response; Immune system; In Vitro; Individual; Laboratories; Light; MHC Class I Genes; Molecular; Nature; Patients; Peptides; Persons; Play; Primates; Process; Property; Proteins; Receptor Cell; Recombinants; Resistance; Role; SIV; Specificity; Structure; Surface Plasmon Resonance; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Ursidae Family; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Viral Physiology; Viral Tumor Antigens; Virus; Walkers; Work; alpha-beta T-Cell Receptor; beta Chain Antigen T Cell Receptor; cohort; combat; cross reactivity; experimental study; improved; insight; killings; macrophage; nonhuman primate; novel; pandemic disease; public health relevance; receptor; receptor binding; response; therapy design; vaccine development; vector

 DESCRIPTION (provided by applicant): This work seeks to understand the basis for CD8 T cell receptor (TCR) recognition of HIV peptide antigens presented by human major histocompatibility complex class II (MHC II) proteins where normally CD8 T cells TCRs recognize antigen presented on MHC class 1. This work was prompted when a successful vaccination against SIV in non-human primates (NHP) demonstrated that in the vaccinated cohort CD8 T cells TCRs were recognizing SIV peptides presented on NHP MHC II and not MHC I. Such a finding raised the hypothesis that healthy uninfected CD8 T cells can usurp the role of virally depleted CD4 T cells during HIV infection to combat HIV. Subsequently Dr Bruce Walker's lab determined that the rare phenomenon of MHC II restricted CD8 T cells occurs in a small percent of human HIV non-progressors who have HIV but do not go on to develop AIDS. Typically these patients have MHC I protective alleles while MHC II HIV protective alleles has not been previously observed. We have partnered with Dr Bruce Walker's lab to determine the details of human HIV non-progressor CD8 TCR restriction to MHC II. We cloned and expressed the specific MHC II (DR11) and the clonal derived TCR from one of these patients. Uncommonly, in this patient's clonal CD8 T cells there are two TCR alpha chains and one shared beta chain. We demonstrated that only one TCR alpha beta (TRAV6) complex recognizes a specific HIV peptide presented by DR11 and that binding leads to T cell activation. We aim to crystallize and solve the structures of these complexes to probe the essential molecular details of this TCR recognition. Additionally we aim to determine the role of the bystander TCR (TRAV26) alpha beta complex in this patients CD8 MHC II restriction. We have already shown that despite not recognizing DR11 presented HIV peptide, TRAV26 does activate T cells. As other TCRs and MHC II restriction arises, from other patient non-progressors, perhaps also with dual TCR alphas, we aim to encompass these into our studies. The longest a HIV non-progressor has survived post HIV infection without anti retro viral therapy is 30 + years. Understanding the mechanisms of how a CD8 T cell can co-opt the role of a CD4 cell in HIV infection could have a significant impact on HIV treatment and vaccine design.

 描述（适用提供）：这项工作旨在了解CD8 T细胞受体（TCR）对人类主要的组织相容性复合物II类（MHC II）蛋白提出的HIV果皮抗原的识别（MHC II）蛋白的基础，通常在MHC类中识别出在MHC 1类中呈现的抗原的CD8 T细胞TCR在MHC 1类中呈现。真空队列CD8 T细胞TCRS识别出在NHP MHC II而不是MHC I.的SIV Pepperides。这种发现提出了以下假设：健康未感染的CD8 T细胞可以利用HIV感染期间病毒耗尽的CD4 T细胞的作用。随后，布鲁斯·沃克（Bruce Walker）博士的实验室确定，MHC II限制的CD8 T细胞的罕见现象出现在患有HIV但不继续发展艾滋病的人类HIV非培训者中。通常，这些患者具有MHC I保护等位基因，而MHC II HIV保护等位基因先前尚未观察到。我们已经与布鲁斯·沃克（Bruce Walker's Lab）博士合作，以确定人类艾滋病毒非促进剂CD8 TCR限制对MHC II的细节。我们克隆并表达了特定的MHC II（DR11），并从其中一名患者克隆了TCR。罕见的是，在该患者的克隆CD8 T细胞中，有两个TCRα链和一个共享β链。我们证明，只有一个TCRαβ（TRAV6）复合物识别DR11呈现的特定HIV肽，并且结合导致T细胞激活。我们旨在将这些复合物的结构结晶和解决，以探测该TCR识别的基本分子细节。此外，我们旨在确定旁观者TCR（TRAV26）αβ复合物在该患者CD8 MHC II限制中的作用。我们已经表明，尽管未识别DR11呈现HIV肽，但TRAV26确实激活了T细胞。正如其他TCR和MHC II限制所产生的一样，其他患者也可能具有双重TCR Alpha，我们的目标是将其纳入我们的研究中。 HIV非培训者最长的艾滋病毒在没有抗复古病毒疗法的HIV感染后幸存了30多年。了解CD8 T细胞如何选择CD4细胞在HIV感染中的作用的机制可能会对HIV治疗和疫苗设计产生重大影响。