The role of NK cells in HIV and tuberculosis co-infection

描述（由申请人提供）：在过去的10年里，我们发表了一系列文章，证明人类NK细胞有潜力促进对结核分枝杆菌的先天和适应性免疫反应。NK细胞裂解结核分枝杆菌感染的肺泡巨噬细胞，产生IL-22，抑制结核分枝杆菌细胞内生长。NK细胞还通过裂解结核分枝杆菌扩增的免疫抑制性CD4+调节性T细胞（Tregs）和上调LTBI患者的CD8+ T细胞反应来增强T细胞反应。我们最近未发表的数据也显示NK细胞有助于t细胞对卡介苗接种的反应。自2007年以来，我们一直与印度海得拉巴LEPRA协会蓝彼得研究中心的Vijaya Valluri博士合作研究NK细胞和treg。根据我们的数据以及我们与Valluri博士团队的合作，我们提出以下目标。1)确定NK细胞对结核分枝杆菌的反应是否在HIV+ LTBI患者中降低。我们将比较有或没有LTBI的HIV-和HIV+患者NK细胞介导M. tb先天应答的能力，并评估有或没有LTBI的HIV-和HIV+患者NK细胞影响t细胞应答的能力。2)确定基于免疫的干预是否可以增强有LTBI和活动性结核病的HIV+患者的NK细胞和t细胞功能。我们将设计干预措施来改善HIV+ LTBI患者的NK细胞功能，确定改善NK细胞功能的干预措施是否也能增强HIV+ LTBI患者的t细胞功能，并确定它们是否能增强HIV+活动性结核病患者的NK细胞和t细胞功能。

DESCRIPTION (provided by applicant): Over the past 10 years, we have published a series of articles demonstrating that human NK cells have the potential to contribute to both innate and adaptive immune responses to M. tb. NK cells lyse M. tb-infected alveolar macrophages and produce IL-22, which inhibits intracellular growth of M. tb. NK cells also enhance T-cell responses by lysing M. tb-expanded immunosuppressive CD4+ regulatory T cells (Tregs) and by upregulating CD8+ T-cell responses in persons with LTBI. Our recent unpublished data also show NK cells contribute to T-cell responses to BCG vaccination. Since 2007, we have been collaborating with Dr. Vijaya Valluri at the Blue Peter Research Center, LEPRA Society, Hyderabad, India on studies of NK cells and Tregs. Based on our data and our established collaboration with Dr. Valluri's group, We propose the following aims. 1) Determine if NK cell responses to M. tb are reduced in HIV+ persons with LTBI. We will compare the capacity of NK cells from HIV- and HIV+ persons, with or without LTBI, to mediate innate responses to M. tb and evaluate the capacity of NK cells from HIV- and HIV+ persons, with or without LTBI, to affect T-cell responses 2) Determine if immune-based interventions can enhance NK cell and T-cell function in HIV+ persons with LTBI and active TB. We will devise interventions to improve NK cell function in HIV+ persons with LTBI, determine if interventions to improve NK cell function also enhance T-cell function in HIV+ persons with LTBI and determine if they enhance NK cell and T-cell function in HIV+ persons with active TB. PUBLIC HEALTH RELEVANCE: Mycobacterium tuberculosis infects one-third of the world's population and causes almost 2 million deaths per year. HIV infection markedly increases susceptibility to TB, and HIV-infected persons with latent tuberculosis infection (LTBI) have an 800-fold greater risk of developing active TB. The proposed studies will improve our understanding of the mechanisms that mediate susceptibility to TB in HIV+ persons, and facilitate development of interventions to improve NK cell function and prevent progression of LTBI in HIV-infected persons.