Intestinal MAIT Cells in HIV Infection

 描述(由申请人提供)： 粘膜相关不变T细胞(MAIT)是近年来发现的一种新的固有类T细胞亚群，在肝脏和粘膜组织中尤为丰富。MAIT细胞表达一种半不变的T细胞受体，该受体由Vα7.2、有限的Jα片段(Jα2、Jα13或Jα20)和有限的Vβ组成。与传统的T细胞不同，MAIT细胞识别MHC-1b相关蛋白MR1提供的微生物代谢物，包括某些细菌和真菌特有的维生素B2(核黄素)代谢物。因为它们在肠道、肝脏等组织中富含 在与艾滋病毒感染特别相关的宿主防御的两个方面，MAIT细胞可能特别重要：促进上皮完整性和限制微生物易位；对分枝杆菌、念珠菌、沙门氏菌等机会性病原体的反应。正如我们小组和其他人最近报道的那样，在慢性HIV感染中，外周血中MAIT细胞水平显著降低。我们假设MAIT的丢失或损害有助于持久的免疫激活，并损害宿主对细菌和真菌病原体的反应。该项目的总体目标是：(A)确定急性和慢性艾滋病毒感染对MAIT细胞的影响，以及(B)确定ART恢复MAIT水平和功能的能力。在目标1中，我们将阐明慢性HIV感染时MAIT细胞丢失和功能障碍的基础。我们将评估HIV感染者和对照组血液中MAIT细胞的水平和功能；解决在慢性HIV感染过程中MAIT细胞丢失的机制；并确定通过抗逆转录病毒治疗(ART)恢复其抗微生物功能的程度。在AIM 2中，我们将确定慢性HIV感染对回肠末端和直肠粘膜MAIT细胞的影响。我们将确定MAIT细胞在这些组织中的丰度和功能，并将在接受抗逆转录病毒治疗和不接受抗逆转录病毒治疗的受试者中，研究MAIT功能与慢性HIV感染免疫激活信号之间的关系。在AIM 3中，我们将确定急性HIV感染时外周和肠道MAIT细胞的动态，并将这些信息与不同的疾病结局和对早期ART的反应联系起来。该项目是一个合作项目，涉及三个合作绩效机构及其实验室：Barbara Shacklett博士(联系加州大学戴维斯分校)、Johan Sandberg博士(卡罗林斯卡研究所)和Michael Eller博士(HJF/MHRP)。该项目涉及艾滋病毒感染者胃肠粘膜免疫受损的机制，是根据RFA-DK-14-019提交的。

 DESCRIPTION (provided by applicant): Mucosa-associated invariant T-cells (MAIT) are a recently characterized, novel subset of innate-like T-cells that are particularly abundant in the liver and mucosal tissues. MAIT cells express a semi-invariant T cell receptor comprised of Vα7.2, limited Jα segments (Jα2, Jα13, or Jα20) an limited Vβ repertoires. Unlike conventional T-cells, MAIT cells recognize microbial metabolites presented by the MHC-1b-related protein MR1, including vitamin B2 (riboflavin) metabolites unique to certain bacteria and fungi. Because of their enrichment in tissues such as the gut, liver and lung, MAIT cells may be particularly important in two aspects of host defense of particular relevance to HIV infection: promoting epithelial integrity and limiting microbial translocation; an responding to opportunistic pathogens such as Mycobacteria, Candida, Salmonella and others. MAIT cell levels in peripheral blood are significantly reduced in chronic HIV infection, as recentl reported by our group and others. We hypothesize that MAIT loss or impairment contributes to persistent immune activation, and compromises host responses to bacterial and fungal pathogens. The overall goals of the project are: (a) to determine the impact of acute and chronic HIV infection on mucosal MAIT cells, and (b) to determine the ability of ART to restore MAIT levels and functionality. IN AIM 1, we will elucidate the basis of MAIT cell loss and dysfunction i chronic HIV infection. We will assess MAIT cell levels and functionality in blood of HIV-infected subjects and controls; address mechanisms by which MAIT cells are lost during chronic HIV infection; and determine the extent to which their antimicrobial functions are restored by antiretroviral therapy (ART). IN AIM 2, we will determine the impact of chronic HIV infection on MAIT cells in terminal ileum and rectal mucosa. We will determine the abundance and functionality of MAIT cells in these tissues, and will address the relationship between MAIT function and immune activation signatures in chronic HIV infection in subjects on and off ART. IN AIM 3, we will determine the dynamics of peripheral and intestinal MAIT cells in acute HIV infection and relate this information to differential disease outcomes and responses to early ART. This project is a collaborative effort involving three Co-PIs and their laboratories: Dr. Barbara Shacklett (contact PI, UC Davis), Dr. Johan Sandberg (Karolinska Institute), and Dr. Michael Eller (HJF/MHRP). The project addresses mechanisms of impaired gastrointestinal mucosal immunity in people with HIV, and is submitted in response to RFA-DK-14-019.