Receptor Diversity in Recognition of Influenza HA

描述(申请人提供)：目标是分析影响因素 调节小鼠CD_4~+T和B细胞的耐受性和自身反应性 表达流感病毒PR8血凝素(HA)的转基因小鼠 特性良好的新自身抗原(HA、TG小鼠)。尤其是，如何 不同的CD4+T和B细胞群体的不同特性会影响 它们由新自我HA进行的负面选择，以及可能导致 将检测HA TG小鼠体内自身反应性淋巴细胞的激活情况。目标1 将研究自身反应性CD4+T细胞的选择和功能潜力 TCRxHA TG小鼠中对自体肽亲和力低的细胞。是否 激活可提高低亲和力T细胞的敏感性 它们对一种自体多肽的反应将被确定。此外，如何 TCR特异性和/或病毒感染与CD4+T细胞的功能有关 HATG小鼠体内表达HA的细胞介导自身免疫性心肌炎 将对心脏组织进行评估。目标2将审查控制 表达特征可变区的B细胞表型潜能 克隆类型，代表对 病毒免疫的BALB/c小鼠体内有血凝素，且对病毒的敏感性不同 HATG小鼠的阴性选择。是否选择进入不同的B细胞 HA的亚集和/或亲和力决定了不同的表型 表达这些克隆型的B细胞的潜力将被评估。在……里面 此外，自身反应性CD4+T细胞是否拯救了最初的反应性B细胞 从删除和/或促进记忆B细胞的形成 将对NEO-SELF HA进行评估。目标3将研究导致 器官特异性自身免疫的发展。一种类似于 在表达HA的TCRxHACII小鼠中发生类风湿关节炎 抗原提呈细胞，以及导致它的细胞相互作用 将对发展情况进行评估。病毒感染是否会引发自身免疫 表达低亲和力CD_4~+T细胞和/或CD_4~+T细胞的TCRxHACII小鼠 指向一种神秘的自体多肽也将被检查。这些研究将 提供对免疫耐受机制的基本见解，并将 与理解导致 自身免疫性疾病的发展。

DESCRIPTION (provided by applicant): The objective is to analyze factors governing tolerance and autoreactivity among murine CD4+ T and B cells in transgenic mice that express the influenza virus PR8 hemagglutinin (HA) as a well-characterized neo-self antigen (HA Tg mice). In particular, how the distinct specificities of separate populations of CD4+ T and B cells affect their negative selection by the neo-self HA, and processes that can lead to the activation of autoreactive lymphocytes in HA Tg mice will be examined. Aim 1 will examine the selection and functional potential of autoreactive CD4+ T cells that have low avidities for a self-peptide in TCRxHA Tg mice. Whether activation increases the sensitivity of low avidity T cells to the extent that they become responsive to a self-peptide will be determined. In addition, how TCR specificity and/or virus infection contributes to the ability of CD4+ T cells to mediate autoimmune myocarditis in HA Tg mice expressing the HA in cardiac tissue will be assessed. Aim 2 will examine factors governing the phenotypic potentials of B cells that express characteristic variable region clonotypes, that are representative of primary versus memory responses to the HA in virus-immunized BALB/c mice, and that differ in their sensitivity to negative selection in HA Tg mice. Whether selection into different B cell subsets and/or affinity for the HA determines the distinct phenotypic potentials of B cells expressing these clonotypes will be evaluated. In addition, whether autoreactive CD4+ T cells rescue primary response B cells from deletion and/or promote memory B cell formation in response to the neo-self HA will be assessed. Aim 3 will examine the processes that lead to the development of organ-specific autoimmunity. An autoimmune syndrome resembling rheumatoid arthritis develops in TCRxHACII mice in which the HA is expressed on antigen presenting cells, and the cellular interactions that lead to its development will be assessed. Whether virus infection provokes autoimmunity in TCRxHACII mice expressing low affinity CD4+ T cells and/or CD4+ T cells directed to a cryptic self-peptide will also be examined. These studies will provide fundamental insights into the mechanisms of immune tolerance, and will have direct relevance to understanding the processes that lead to the development of autoimmune disease.