Role of CD8IL-13 T cells in Chlamydia infection-associated immunopathology

CD8IL-13 T 细胞在衣原体感染相关免疫病理学中的作用

• 批准号: 9056430
• 负责人: RAYMOND Morris JOHNSON
• 金额: $ 20.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056430
• 关键词: Adolescent; Adolescent and Young Adult; Adoptive Transfer; Antibiotic Therapy; Antigens; Applications Grants; Biological Markers; CD4 Positive T Lymphocytes; CD8B1 gene; Cell surface; Cells; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Cicatrix; Clinical Trials; Consensus Development; Data; Development; Ectopic Pregnancy; Epitope Mapping; Europe; Event; Eye Infections; Fostering; Future; Gene Expression Microarray Analysis; Health; Human; Immune; Immune response; Immunity; Immunobiology; Incidence; Individual; Infection; Infection prevention; Infertility; Interferons; Interleukin-10; Interleukin-13; Investigation; Laboratories; Literature; Mediating; Mediator of activation protein; Molecular Profiling; Mononuclear; Mus; Outcome; Pathway interactions; Pattern; Peripheral; Play; Population; Prevalence; Production; Proteins; Public Health; Research; Resolution; Role; Safety; Source; Splenocyte; Subunit Vaccines; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Therapeutic Intervention; Trachoma; Tubal Pregnancy; Vaccines; Western Europe; Whole Organism; Woman; base; biomarker identification; cell type; cytokine; immunopathology; insight; mouse model; novel; peripheral blood; reproductive tract; targeted treatment; trachoma vaccine; vaccine candidate; young adult

DESCRIPTION (provided by applicant): Chlamydia trachomatis genital tract infections have a prevalence of 2-15% in adolescents/young adults in the USA and Europe in spite of public health efforts and effective antibiotic therapy. It is widely accepted that a vaccine is necessary reduce its prevalence. An early C.trachomatis trachoma (eye infection) vaccine delivered poor protection and exacerbated immunopathology. Critical to developing a safe Chlamydia vaccine is a better understanding of immunopathology. Currently there are no practicable biomarkers for Chlamydia immunopathology. In the C. muridarum mouse model others have clearly shown that Chlamydia-specific CD8 T cells are important mediators of immunopathology and infertility. We have recently shown that a subset of Chlamydia-specific CD8 T cell clones derived from mice that self-cleared C. muridarum genital tract infections produce the scar-ogenic cytokines IL-10, TNF�nd IL-13. These CD8 clones are not restricted by MHC class Ia molecules. Similar non-class Ia restricted CD8 T cell clones have been derived from the peripheral blood of humans with C. trachomatis genital tract infections. Using gene expression microarray analysis we have identified a molecular fingerprint for CD8IL-13 T cells. Based on the existing mouse and human Chlamydia literature it clear that the cellular immune response to Chlamydia genital tract infections includes non-class Ia restricted CD8 T cells. The C. muridarum mouse model has unequivocally shown CD8 T cells to be mediators of immunopathology and infertility. We hypothesize that the mechanism underlying CD8 immunopathology is a non-MHC class Ia restricted CD8 T subset secreting IL-10, TNF�and IL-13. To test that hypothesis and investigate the underlying immunobiology we propose the following specific aims: Specific aim #1- to investigate the role of CD8IL-13 T cells in immunopathology utilizing adoptive transfer. We have representative conventional Chlamydia-specific CD8 T cell clones, Chlamydia-specific CD8IL-13 T cell clones, and putative cell surface biomarkers for purifying CD8IL-13 T cells from immune splenocytes or bulk T cell populations. Specific aim #2- to investigate the activation pathway and other immunobiology specific to Chlamydia-specific CD8IL-13 T cells. Utilizing existing T cell clones and gene expression microarray analysis we will compare activated conventional CD8 with activated CD8IL-13 T cells to identify CD8IL-13 specific immunobiology; potentially identifying additional biomarkers and targets for therapeutic intervention. We will als map the epitope source proteins for the Chlamydia-specific CD8 T cell clone panel. Specific aim #3- perform a preliminary investigation of CD8IL-13 T cells in humans. Using putative biomarkers for the CD8IL-13 T cell subset identified in the mouse model we will isolate CD8 T cells from the peripheral blood of healthy individuals and determine whether a similar CD8IL-13 T cell subset exists in humans.

描述（由适用提供）：尽管有公共卫生努力和有效的抗生素治疗，但在美国/年轻人中，青少年/年轻人的沙丘瘤生殖道感染的患病率为2-15％。人们普遍认为，有必要降低其患病率。早期的C. c. throchomatis沙眼（眼部感染）疫苗提供了不良的保护和恶化的免疫病理学。对安全衣原体疫苗开发至关重要的是对免疫病理学的更好理解。目前，没有用于衣原体免疫病理学的实用生物标志物。在Muridarum C. house模型中，其他人清楚地表明，衣原体特异性的CD8 T细胞是免疫病理学和不育的重要介体。我们最近表明，从小鼠衍生出的一部分衣原体特异性CD8 T细胞克隆，即自被清除的Muridarum生殖道感染产生疤痕源性细胞因子IL-10，TNF。这些CD8克隆不受MHC类IA分子的限制。类似的非类IA限制的CD8 T细胞克隆已从人体的外周血中得出，并具有沙眼梭状芽孢杆菌，生殖道感染。使用基因表达微阵列分析，我们已经确定了CD8IL-13 T细胞的分子指纹。基于现有的小鼠和人类衣原体文献，明确的是，对衣原体生殖道感染的细胞免疫响应包括非级别的IA限制CD8 T细胞。 Muridarum小鼠模型明确显示了CD8 T细胞是免疫病理学和不育的介体。我们假设CD8免疫病理学的基础机制是非MHC IA类限制的CD8 T子集分泌IL-10，TNF和IL-13。为了检验该假设并研究潜在的免疫生物学，我们提出了以下特定目的：特定目的1-研究CD8IL-13 T细胞在利用适应性转移的免疫病理学中的作用。我们拥有代表性的常规衣原体特异性CD8 T细胞克隆，衣原体特异性CD8IL-13 T细胞克隆和假定的细胞表面生物标志物，用于从免疫异胞列细胞或散装T细胞群中净化CD8IL-13 T细胞。具体目的＃2-研究激活途径和其他针对衣原体特异性CD8IL-13 T细胞的免疫生物学。利用现有的T细胞克隆和基因表达微阵列分析，我们将与活化的常规CD8与活化的CD8IL-13 T细胞进行比较，以鉴定CD8IL-13特异性免疫生物学；有可能识别用于治疗干预的其他生物标志物和靶标。我们将为衣原体特异性CD8 T细胞克隆面板绘制ALS的表位源蛋白。特定目标＃3-对人类中CD8IL-13 T细胞进行初步投资。使用小鼠模型中鉴定的CD8IL-13 T细胞子群的假定生物标志物，我们将与健康个体的外周血分离CD8 T细胞，并确定人类中是否存在类似的CD8IL-13 T细胞子集。