Effector and Memory Anti-Malaria CD8+ Cell Responses

效应器和记忆抗疟疾 CD8 细胞反应

• 批准号: 6839926
• 负责人: FIDEL P ZAVALA
• 金额: $ 54.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839926
• 关键词: Plasmodium; T cell receptor; cellular immunity; cytoprotection; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; epitope mapping; genetically modified animals; growth inhibitors; helper T lymphocyte; immunologic memory; laboratory mouse; malaria; polymerase chain reaction

DESCRIPTION (provided by the applicant): CD8+ T cells play a major protective role in immunity to malaria infection by inhibiting the development of liver stages. Vaccination studies using malaria sporozoites as well as viral vectors, DNA or synthetic constructs expressing malaria antigens have provided important new information regarding the protective role of these T cells. It was shown that mice immunized with different vectors expressing the same plasmodial sequence induce malaria-specific CD8+ T cells, which strongly inhibit liver stage development, conferring sterile immunity to a significant proportion of the immunized mice. More recently, we demonstrated that the induction of these T cell responses fully depends on IL-4 secreting CD4+ T cells. These studies have raised a number of important questions with regard to the nature of the factors mediating CD4+/CD8+ T cell cross talk and to the mechanisms which regulate the induction and development of effector and memory CD8+ T cell responses. We propose to undertake studies aimed at characterizing some basic aspects of the in vivo CD8+ T cell responses against the liver stages of P. yoelii. We propose investigations aimed at defining basic parameters of CD4+/CD8+ T cell cross talk and identifying the cellular and molecular mechanisms underlying the helper effect of CD4+ T cells. We also propose to characterize the recall memory CDS+ T cell responses with regard to the effector mechanisms used by memory cells to inhibit parasite development and the regulatory mechanisms that control the in vivo expansion of memory CD8+ T cells, upon reencounter with parasite antigen. For these studies, we have generated transgenic mice expressing a T cell receptor specific for a CD8+ T cell epitope and another expressing a TCR specific for a CD4+ T cell epitope. Both epitopes are recognized by T cells that inhibit parasite development and are located in the P. yoelii CS protein. The availability of these TCR transgenic mice will allow the use of large numbers of monoclonal T cell populations for in vivo studies, greatly facilitating the characterization of functional and molecular properties of T cells before and after encountering parasite antigen, and through the differentiation process from activated to memory T cells.

描述（由申请人提供）：CD8+ T细胞通过抑制肝脏阶段的发展在免疫对疟疾感染中起主要保护作用。使用疟疾孢子虫以及表达疟疾抗原的DNA或合成构建体的疫苗接种研究提供了有关这些T细胞保护作用的重要新信息。结果表明，用表达相同质粒序列的不同载体免疫的小鼠会诱导疟疾特异性的CD8+ T细胞，从而强烈抑制肝脏阶段的发育，从而赋予无菌免疫，从而将无菌的小鼠免疫。最近，我们证明了这些T细胞反应的诱导完全取决于IL-4分泌CD4+ T细胞。这些研究提出了许多重要的问题，就介导CD4+/CD8+ T细胞串扰的因素的性质以及调节效应子和记忆CD8+ T细胞反应的诱导和发展的机制。我们建议进行旨在表征体内CD8+ T细胞反应的一些基本方面的研究，以针对P. yoelii的肝脏阶段进行表征。我们提出的研究旨在定义CD4+/CD8+ T细胞串联的基本参数，并确定CD4+ T细胞辅助效应的细胞和分子机制。我们还建议在记忆细胞在使用寄生虫抗原的重新遇到后，以记忆细胞抑制寄生虫发育的效应机制和控制体内扩展的体内扩展CD8+ T细胞的调节机制来表征回忆记忆CDS+ T细胞反应。在这些研究中，我们已经产生了表达针对CD8+ T细胞表位的T细胞受体的转基因小鼠，而另一种表达对CD4+ T细胞表位的TCR。这两个表位都被抑制寄生虫发育的T细胞识别，并位于P. yoelii CS蛋白中。这些TCR转基因小鼠的可用性将允许使用大量的单克隆T细胞群来进行体内研究，从而大大促进了T细胞在遇到寄生虫抗原之前和之后的功能和分子特性的表征，以及通过激活过程到记忆T细胞的分化过程。