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

 描述（由申请人提供）：本工作旨在了解CD8 T细胞受体（TCR）识别由人主要组织相容性复合体II类（MHC II）蛋白呈递的HIV肽抗原的基础，其中通常CD8 T细胞TCR识别MHC 1类上呈递的抗原。当在非人灵长类动物（NHP）中针对SIV的成功疫苗接种证明在疫苗接种的组群中CD8 T细胞TCR识别NHP MHC II而非MHC I上呈递的SIV肽时，该工作被促进。这一发现提出了一个假设，即健康的未感染的CD8 T细胞可以在HIV感染期间篡夺病毒耗尽的CD4 T细胞的作用，以对抗HIV。随后，布鲁斯步行者博士的实验室确定，MHC II限制性CD8 T细胞的罕见现象发生在一小部分患有艾滋病毒但不会继续发展为艾滋病的人类艾滋病毒非进展者中。通常这些患者具有MHC I保护性等位基因，而MHC II HIV保护性等位基因先前未观察到。我们已经与布鲁斯博士步行者的实验室合作，以确定人类艾滋病毒非进展CD8 TCR限制MHC II的细节。我们克隆并表达了特异性MHC II（DR 11）和克隆来源于这些患者之一的TCR。罕见的是，在该患者的克隆CD8 T细胞中，存在两条TCR α链和一条共享β链。我们证明，只有一个TCR α β（TRAV6）复合物识别由DR11呈递的特定HIV肽，并且结合导致T细胞活化。我们的目标是结晶和解决这些复合物的结构，以探测这种TCR识别的基本分子细节。此外，我们的目标是确定旁观者TCR（TRAV26）α β复合物在该患者CD8 MHC II限制中的作用。我们已经证明，尽管不识别DR11呈递的HIV肽，TRAV 26确实激活T细胞。由于其他TCR和MHC II限制的出现，来自其他患者的非进展者，可能也具有双重TCR α，我们的目标是将这些纳入我们的研究。在没有抗逆转录病毒治疗的情况下，艾滋病毒非进展者在艾滋病毒感染后存活的最长时间为30年以上。了解CD8 T细胞如何在HIV感染中吸收CD4细胞的作用的机制可能对HIV治疗和疫苗设计产生重大影响。

 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.