NK cell-mediated regulation of T cell immunity in TB/HIV co-infection

描述(由申请人提供)： 世界上三分之一的人口感染了结核分枝杆菌，1000多万人同时感染了人类免疫缺陷病毒(HIV)。潜伏的结核分枝杆菌感染(LTBI)代表免疫遏制，然而，艾滋病毒感染会增加LTBI重新激活的风险，从未感染艾滋病毒的人的5-10%的终身风险增加到艾滋病毒阳性的人的每年10%的风险。HIV相关的先天免疫调节失调和CD4T辅助细胞耗尽导致的获得性免疫功能受损可能是导致LTBI免疫控制丧失和HIV合并感染者发展为结核病的原因之一。然而，在HIV合并感染的背景下，LTBI的免疫控制参数尚未确定。对结核分枝杆菌在人类和动物模型中感染的研究表明，先天免疫和获得性免疫，特别是T细胞，对LTBI的免疫控制至关重要。有趣的是，最近的证据表明，先天性免疫细胞在调节抗原特异性T细胞反应中发挥着重要作用。自然杀伤(NK)细胞通过直接机制，如裂解活化的和/或抗原特异性的CD4和CD8T细胞，以及间接机制，如编辑启动效应T细胞反应的树突状细胞群，以及限制抗原提呈细胞的刺激能力，来调节抗原特异性T细胞 抗原特异性T细胞增殖。因此，先天免疫细胞可以塑造抗原特异性T细胞对病原体的反应。这项建议的重点是研究先天免疫反应如何调节结核分枝杆菌特异性T细胞免疫，并确定在HIV合并感染的情况下，将先天免疫和获得性免疫与结核分枝杆菌联系起来的调节途径是如何受到干扰的。我们建议检验假设：(1)NK细胞调节结核分枝杆菌特异性记忆T细胞的表型和功能，以及(2)与HIV混合感染通过促进结核分枝杆菌特异性CD4和CD8 T细胞的NK细胞裂解，扰乱NK细胞对结核分枝杆菌特异性记忆T细胞反应的调节，从而导致LTBI免疫控制的丧失，并增加HIV/结核分枝杆菌混合感染者发展为结核病的风险。我们建议(1)确定LTBI和HIV合并感染患者的表型、功能能力和NK细胞受体基因型别；(2)确定NK细胞类型与结核分枝杆菌特异性CD4和CD8 T细胞反应的表型和功能之间的关系；(3)确定NK细胞调节结核分枝杆菌特异性CD4和CD8 T细胞免疫的直接和间接机制，以及在HIV合并感染的背景下NK细胞和结核分枝杆菌特异性T细胞之间的相互作用机制是如何失调的。明确参与产生、维持和调节对结核分枝杆菌感染的保护性记忆T细胞反应的免疫途径，并确定艾滋病毒感染损害对结核分枝杆菌的保护性T细胞免疫的机制，对于促进有效的结核病疫苗的开发和针对性的免疫治疗干预以及对艾滋病毒和结核分枝杆菌混合感染者的治疗至关重要，这是遏制全球结核病流行所必需的。

DESCRIPTION (provided by applicant): One third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and over 10 million are co-infected with human immunodeficiency virus (HIV). Latent Mtb infection (LTBI) represents immune containment, however HIV infection increases the risk of reactivation of LTBI from a 5-10% lifetime risk in HIV- uninfected individuals to a 10% annual risk in HIV-positive individuals. HIV-associated dysregulation of innate immunity and impairment of adaptive immunity by depletion of CD4 T helper cells likely contribute to loss of immune control of LTBI and progression to TB disease in HIV co-infected individuals. However, the parameters of immune control of LTBI that are perturbed in the setting of HIV co-infection have not been defined. Studies of Mtb infection in humans and animal models have demonstrated that both innate and adaptive immunity, particularly T cells, are critical for immune control of LTBI. Interestingly, recent evidence indicates innate immune cells play an important role in modulating antigen-specific T cell responses. Natural killer (NK) cells have been shown to modulate antigen-specific T cells by direct mechanisms, such as lysis of activated and/or antigen-specific CD4 and CD8 T cells, and indirect mechanisms, such as editing dendritic cell populations that prime effector T cell responses, and limiting the capacity of antigen presenting cells to stimulate antigen- specific T cell proliferation. Thus, innate immune cells can shape the profiles of antigen-specific T cell responses to a pathogen. The focus of this proposal is to examine how the innate immune response modulates Mtb-specific T cell immunity and determine how the regulatory pathways linking innate and adaptive immunity to Mtb are perturbed in the setting of HIV co-infection. We propose to test the hypotheses that (1) NK cells modulate the phenotype and functional profile of Mtb-specific memory T cells, and (2) that co-infection with HIV perturbs NK cell-mediated regulation of Mtb-specific memory T cell responses by promoting NK cell lysis of Mtb-specific CD4 and CD8 T cells, thereby contributing to loss of immune control of LTBI and increased risk of progression to TB disease in HIV/Mtb co-infected individuals. We propose to (1) define the phenotypic profiles, functional capacities, and NK cell receptor genotypes in persons with LTBI and HIV co-infection; (2) determine the relationship between NK cell profiles and the phenotype and function of Mtb-specific CD4 and CD8 T cell responses; and (3) define the direct and indirect mechanisms whereby NK cells modulate Mtb-specific CD4 and CD8 T cell immunity in LTBI, and how the mechanisms of cross-talk between NK cells and Mtb-specific T cells are dysregulated in the setting of HIV co-infection. Defining immune pathways involved in the generation, maintenance, and regulation of protective memory T cell responses to Mtb infection, and identifying the mechanisms whereby HIV infection impairs protective T cell immunity to Mtb, will be of vital importance to facilitate development of effective TB vaccines and targeted immunotherapeutic interventions and treatment of individuals co-infected with HIV and Mtb that are necessary to curb the TB epidemic worldwide.