The role of non-classical MHC class I molecules in immune responses to Mycobacterium tuberculosis infection

非经典 MHC I 类分子在结核分枝杆菌感染免疫反应中的作用

• 批准号: 10402266
• 负责人: Chyung-Ru Wang
• 金额: $ 56.74万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-14 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402266
• 关键词: Activities of Daily Living; Adoptive Transfer; Animal Model; Antigen Presentation; Antigens; Attenuated; Autoimmune Diseases; Bacterial Model; Biological Assay; Biological Response Modifiers; CD8-Positive T-Lymphocytes; CD8B1 gene; Characteristics; Development; Elements; Equilibrium; Exhibits; Flow Cytometry; Frequencies; Future; Gene Expression Profile; Generations; Genetic; Glycopeptides; HLA G antigen; Histocompatibility Antigens Class I; Homologous Gene; Host Defense; Human; Immune response; Immunity; Immunodominant Antigens; Immunologic Memory; In Vitro; Individual; Interruption; KLRD1 gene; Kinetics; Knowledge; Lead; MHC antigen; Mediating; Memory; Modeling; Mouse Strains; Mucous Membrane; Mus; Mutant Strains Mice; Mycobacterium Infections; Mycobacterium tuberculosis; Mycobacterium tuberculosis H37Rv; Mycobacterium tuberculosis antigens; Peptides; Phenotype; Play; Population; Predisposition; Preventive vaccine; Property; Proteins; Pulmonary Pathology; Qa-1 Antigen; Receptor Activation; Regulatory T-Lymphocyte; Role; Surface; T cell regulation; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Thymus Gland; Tuberculosis; Vaccination; Vaccines; Virulent; Virus Diseases; Vitamin B Complex; base; cytotoxic CD8 T cells; microorganism antigen; mouse model; mycobacterial; novel; peptide vaccination; prevent; protective efficacy; receptor; response; transcriptome sequencing; tuberculosis immunity; vaccination against tuberculosis; vaccination strategy; vaccine candidate; vaccine development; vaccine strategy

PROJECT SUMMARY While current Mycobacterium tuberculosis (Mtb) vaccine development has primarily focused on CD4+ and MHC Ia-restricted CD8+ T cell responses, increasing evidence shows that non-conventional CD8+ T cells restricted by MHC Ib molecules can recognize diverse microbial antigens and contribute to protection against Mtb infection. For example, H2-M3, Qa-1/HLA-E, Qa-2/HLA-G, MR1, and CD1 have been implicated in the host immune response against Mtb in mice and/or humans. However, most of these studies have only examined the function of MHC Ib-restricted T cells during the primary response to Mtb infection. Given that several subsets of MHC Ib- restricted T cells exhibit "innate-like" T cell characteristics and undergo unique thymic selection, it is unclear whether and which MHC Ib-restricted CD8+ T cell population can mount a memory response during Mtb infection. Furthermore, some MHC Ib molecules also act as regulators of the immune responses aside from their role in antigen presentation. In particular, Qa-1 can regulate immune responses against Mtb through the interaction with inhibitory CD94/NKG2A receptors and regulatory CD8+ T cells. To better understand the diverse role of MHC Ib molecules play in immune responses against Mtb, this proposal seeks to determine whether the composition and function of MHC Ib-restricted CD8+ T cell subsets in the secondary response differs from the primary response, as well as how individual Qa-1-mediated regulatory mechanisms contribute to the immune response against Mtb. In Aim 1, we propose to compare the kinetics, function, and protective ability of MHC Ib- restricted CD8+ T cell responses during primary and secondary Mtb infection in mice, and evaluate the protective efficacy of vaccination with Qa-1/HLA-E-restricted Mtb peptides. We will use a novel vaccination and re- challenge model that allows for complete clearance of an attenuated Mtb strain prior to challenge with fully virulent Mtb to study memory responses. These studies will allow us to identify the dominant MHC Ib-restricted CD8+ T cells and the Mtb antigens they present during the secondary immune response, their ability to mediate protective immunity against Mtb, and peptide vaccination strategies to increase the frequency of these effector CD8+ T cells. In Aim 2, we propose to investigate the mechanisms by which Qa-1 regulates immune responses during Mtb infection, with a focus on how inhibitory CD94/NKG2A receptors and suppressive Qa-1-restricted CD8+ Tregs individually contribute to the regulation of T cell responses during Mtb infection. To study these mechanisms, we will use mouse strains with genetic interruption of Qa-1’s interaction with individual receptors. These studies will allow us to identify how Qa-1 is able contribute to the balance between effector and regulatory immune responses for better protective immunity against Mtb. The combined results from our studies will yield a better understanding of how MHC Ib molecules and MHC Ib-restricted T cells contribute to the overall immune response against Mtb, for the development of better future vaccine strategies.

项目摘要 虽然目前结核分枝杆菌（Mtb）疫苗的开发主要集中在CD 4+和MHC Ia限制性CD 8 + T细胞应答，越来越多的证据表明，受Ia限制的非常规CD 8 + T细胞 MHC Ib分子可以识别多种微生物抗原，并有助于保护免受Mtb感染。 例如，H2-M3、Qa-1/HLA-E、Qa-2/HLA-G、MR 1和CD 1已经涉及宿主免疫应答。 在小鼠和/或人中抗Mtb的应答。然而，这些研究中的大多数仅检查了 在对Mtb感染的初级应答期间，MHC-Ib-限制性T细胞。考虑到MHC Ib的几个子集- 限制性T细胞表现出“先天性”T细胞特征，并经历独特的胸腺选择，目前尚不清楚 在Mtb感染期间，MHCIb限制性CD 8 + T细胞群是否以及哪种可以产生记忆应答。 此外，一些MHC Ib分子除了在免疫反应中发挥作用外，还充当免疫反应的调节剂。 抗原呈递特别地，Qa-1可以通过与Mtb的相互作用来调节针对Mtb的免疫应答。 抑制性CD 94/NKG 2A受体和调节性CD 8 + T细胞。为了更好地理解不同的角色， MHC Ib分子在抗结核分枝杆菌的免疫反应中起作用，这项提议试图确定MHC Ib分子是否在抗结核分枝杆菌的免疫反应中起作用。 MHC Ib限制性CD 8 + T细胞亚群在继发性应答中的组成和功能不同于 主要反应，以及如何个人Qa-1介导的调节机制有助于免疫 对结核分枝杆菌的反应在目的1中，我们提出比较MHC Ib-1的动力学、功能和保护能力。 在小鼠中，在原发性和继发性Mtb感染期间，限制性CD 8 + T细胞应答，并评估保护性Mtb抗体的作用。 用Qa-1/HLA-E限制性Mtb肽接种的效力。我们将使用一种新的疫苗， 攻击模型，其允许在用完全抗结核抗体攻击之前完全清除减毒的Mtb菌株。 致命的结核分枝杆菌来研究记忆反应这些研究将使我们能够确定占主导地位的MHC Ib限制性 CD 8 + T细胞和它们在二次免疫应答期间呈递的Mtb抗原，它们介导免疫应答的能力， 针对Mtb的保护性免疫，以及增加这些效应子的频率的肽疫苗接种策略。 CD 8 + T细胞。在目的2中，我们提出研究Qa-1调节免疫应答的机制 在Mtb感染期间，重点关注抑制性CD 94/NKG 2A受体和抑制性Qa-1限制性 CD 8 + T淋巴细胞在结核分枝杆菌感染过程中单独参与调节T细胞应答。研究这些 为了进一步研究Qa-1的作用机制，我们将使用具有Qa-1与单个受体相互作用的遗传中断的小鼠品系。 这些研究将使我们能够确定Qa-1如何能够促进效应和调节之间的平衡。 免疫应答以获得针对Mtb的更好的保护性免疫。综合我们的研究结果 更好地理解MHC Ib分子和MHC Ib限制性T细胞如何促进整体免疫 对结核分枝杆菌的反应，为更好的未来疫苗战略的发展。