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）。潜伏性Mtb感染（LTBI）代表免疫遏制，然而HIV感染增加了LTBI再激活的风险，从HIV未感染个体的5-10%终身风险增加到HIV阳性个体的10%年风险。HIV相关的先天免疫失调和CD 4辅助性T细胞耗竭导致的适应性免疫受损可能导致LTBI免疫控制丧失，并导致HIV合并感染个体进展为TB疾病。然而，在HIV合并感染的情况下受到干扰的LTBI的免疫控制参数尚未确定。在人类和动物模型中对Mtb感染的研究表明，先天性和适应性免疫，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细胞应答中起重要作用。已经显示自然杀伤（NK）细胞通过直接机制（例如活化的和/或抗原特异性CD 4和CD 8 T细胞的裂解）和间接机制（例如编辑引发效应T细胞应答的树突细胞群和限制抗原呈递细胞刺激免疫应答的能力）来调节抗原特异性T细胞。 抗原特异性T细胞增殖。因此，先天性免疫细胞可以塑造抗原特异性T细胞对病原体的应答的特征。该提案的重点是研究先天免疫应答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，将先天免疫和适应性免疫与结核分枝杆菌联系起来的调节途径如何受到干扰。我们提出检验以下假设：（1）NK细胞调节Mtb特异性记忆T细胞的表型和功能谱，以及（2）与HIV共感染通过促进NK细胞溶解Mtb特异性CD 4和CD 8 T细胞，扰乱NK细胞介导的Mtb特异性记忆T细胞应答的调节，从而在HIV/Mtb共感染的个体中导致LTBI的免疫控制丧失和进展为TB疾病的风险增加。本研究拟（1）明确LTBI和HIV共感染者的表型特征、功能能力和NK细胞受体基因型;（2）确定NK细胞特征与Mtb特异性CD 4和CD 8 T细胞应答的表型和功能之间的关系;和（3）确定NK细胞调节LTBI中Mtb特异性CD 4和CD 8 T细胞免疫的直接和间接机制，以及NK细胞和Mtb特异性T细胞之间的相互作用机制如何在HIV合并感染的情况下失调。定义参与对Mtb感染的保护性记忆T细胞应答的产生、维持和调节的免疫途径，并确定HIV感染损害对Mtb的保护性T细胞免疫的机制，这对于促进有效结核病疫苗和有针对性的免疫干预措施的开发以及对艾滋病毒和结核病合并感染者的治疗至关重要，这对于遏制全球结核病流行是必要的。

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.