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

描述（由申请人提供）：尽管公共卫生努力和有效的抗生素治疗，在美国和欧洲的青少年/年轻人中，沙眼衣原体生殖道感染的患病率为2-15%。人们普遍认为疫苗是必要的，以减少其流行。早期沙眼原体（眼部感染）疫苗保护效果不佳，并加重了免疫病理。开发安全的衣原体疫苗的关键是更好地了解免疫病理学。目前还没有可行的衣原体免疫病理学生物标志物。在C. muridarum小鼠模型中，其他人已经清楚地表明衣原体特异性CD8 T细胞是免疫病理和不育的重要介质。我们最近的研究表明，来自自清除C. muridarum生殖道感染的小鼠的衣原体特异性CD8 T细胞克隆亚群产生疤痕源性细胞因子IL-10， TNF -和IL-13。这些CD8克隆不受MHC Ia类分子的限制。类似的非Ia类限制性CD8 T细胞克隆已从沙眼衣原体生殖道感染患者的外周血中获得。利用基因表达微阵列分析，我们已经鉴定出CD8IL-13 T细胞的分子指纹图谱。基于现有的小鼠和人类衣原体文献，清楚地表明，对衣原体生殖道感染的细胞免疫应答包括非Ia类限制性CD8 T细胞。C. muridarum小鼠模型明确显示CD8 T细胞是免疫病理和不育的介质。我们假设CD8免疫病理的机制是一个非mhc Ia类限制CD8 T亚群分泌IL-10、TNF -和IL-13。为了验证这一假设并研究潜在的免疫生物学，我们提出了以下具体目标：具体目标#1-利用过继性转移研究CD8IL-13 T细胞在免疫病理学中的作用。我们有代表性的传统衣原体特异性CD8 T细胞克隆，衣原体特异性CD8IL-13 T细胞克隆，以及用于从免疫脾细胞或散装T细胞群中纯化CD8IL-13 T细胞的假定的细胞表面生物标志物。特异性目的#2-研究衣原体特异性CD8IL-13 T细胞的激活途径和其他免疫生物学特异性。利用现有的T细胞克隆和基因表达微阵列分析，我们将比较活化的常规CD8和活化的CD8IL-13 T细胞，以鉴定CD8IL-13特异性免疫生物学；潜在地确定治疗干预的其他生物标志物和靶点。我们还将绘制衣原体特异性CD8 T细胞克隆面板的表位源蛋白。具体目标#3-对人类CD8IL-13 T细胞进行初步研究。利用在小鼠模型中鉴定的CD8IL-13 T细胞亚群的假定生物标志物，我们将从健康个体的外周血中分离CD8 T细胞，并确定人类中是否存在类似的CD8IL-13 T细胞亚群。

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.