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

TB/HIV 共感染中 NK 细胞介导的 T 细胞免疫调节

• 批准号: 8707104
• 负责人: Cheryl Liane Day
• 金额: $ 66.46万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707104
• 关键词: Activities of Daily Living; Acute; Address; Animal Model; Antigen-Presenting Cells; Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Clinical; Containment; Cytolysis; Dendritic Cells; Development; Disease; Epidemic; Generations; Genotype; Goals; HIV; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; Immunocompetent; Immunosuppression; Immunotherapeutic agent; Impairment; Individual; Infection; Intervention; Kenya; Life; Link; Maintenance; Mediating; Memory; Mycobacterium tuberculosis; Natural Immunity; Natural Killer Cells; Pathway interactions; Persons; Phenotype; Play; Population; Regulation; Regulatory Pathway; Risk; Risk Factors; Role; Shapes; Symptoms; T cell regulation; T cell response; T memory cell; T-Cell Proliferation; T-Lymphocyte; Testing; Tuberculosis; Tuberculosis Vaccines; Viral Load result; Virus Diseases; adaptive immunity; cohort; design; insight; lifetime risk; novel; pathogen; prevent; public health relevance; receptor; response; vaccine development

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.

描述（由申请人提供）： 世界上三分之一的人口感染结核分枝杆菌 (Mtb)，超过 1000 万人同时感染人类免疫缺陷病毒 (HIV)。潜伏结核分枝杆菌感染 (LTBI) 代表免疫抑制，但 HIV 感染会增加 LTBI 重新激活的风险，从未感染 HIV 的个体终生风险为 5-10%，而 HIV 阳性个体的每年风险为 10%。 HIV 相关的先天免疫失调和 CD4 T 辅助细胞耗竭导致的适应性免疫受损可能导致 HIV 合并感染者失去 LTBI 免疫控制并进展为结核病。然而，在 HIV 合并感染的情况下受到干扰的 LTBI 免疫控制参数尚未确定。对人类和动物模型中 Mtb 感染的研究表明，先天免疫和适应性免疫，特别是 T 细胞，对于 LTBI 的免疫控制至关重要。有趣的是，最近的证据表明先天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) 细胞已被证明可以通过直接机制（例如裂解活化的和/或抗原特异性 CD4 和 CD8 T 细胞）和间接机制（例如编辑启动效应器的树突细胞群）来调节抗原特异性 T 细胞T 细胞反应，并限制抗原呈递细胞刺激的能力 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特征。该提案的重点是研究先天免疫反应如何调节 Mtb 特异性 T 细胞免疫，并确定在 HIV 合并感染的情况下，连接先天免疫和适应性免疫与 Mtb 的调节途径如何受到干扰。我们建议测试以下假设：(1) NK 细胞调节 Mtb 特异性记忆 T 细胞的表型和功能特征，以及 (2) 与 HIV 共感染扰乱 NK 细胞介导的 Mtb 特异性记忆 T 细胞反应的调节通过促进 NK 细胞裂解 Mtb 特异性 CD4 和 CD8 T 细胞，从而导致 LTBI 免疫控制丧失，并增加 HIV/Mtb 进展为结核病的风险共同感染者。我们建议 (1) 定义 LTBI 和 HIV 双重感染者的表型特征、功能能力和 NK 细胞受体基因型； (2)确定NK细胞谱与Mtb特异性CD4和CD8 T细胞反应的表型和功能之间的关系； (3) 定义 NK 细胞在 LTBI 中调节 Mtb 特异性 CD4 和 CD8 T 细胞免疫的直接和间接机制，以及 NK 细胞和 Mtb 特异性 T 细胞之间的串扰机制在 HIV 环境中如何失调共同感染。定义涉及 Mtb 感染的保护性记忆 T 细胞反应的产生、维持和调节的免疫途径，并确定 HIV 感染损害 Mtb 的保护性 T 细胞免疫的机制，对于促进有效的 TB 疫苗和疫苗的开发至关重要。对艾滋病毒和结核分枝杆菌合并感染者进行有针对性的免疫治疗干预和治疗，这对于遏制全球结核病流行是必要的。