Receptor Diversity in Recognition of Influenza HA

描述（由申请人提供）：目的是分析因素 调节小鼠CD 4 + T和B细胞之间的耐受性和自身反应性， 将流感病毒PR 8血凝素（HA）表达为 良好表征的新自身抗原（HA Tg小鼠）。特别是， CD 4 + T和B细胞的不同群体的不同特异性影响 他们的负选择的新自我HA，和过程，可以导致 将检测HA Tg小鼠中自身反应性淋巴细胞的活化。要求1 将研究自身反应性CD 4 + T细胞的选择和功能潜力， 在TCRxHA Tg小鼠中对自身肽具有低亲合力的细胞。是否 活化增加了低亲合力T细胞的敏感性， 将确定它们对自身肽的应答。此外，如何 TCR特异性和/或病毒感染有助于CD 4 + T细胞的能力， 细胞介导的自身免疫性心肌炎在HA Tg小鼠中表达HA， 将评估心脏组织。目标2将审查 表达特征性可变区的B细胞的表型潜能 克隆型，其代表了对免疫缺陷病毒的主要与记忆反应。 HA在病毒免疫的BALB/c小鼠中，并且它们对 在HA Tg小鼠中的阴性选择。是否选择进入不同的B细胞 HA的亚群和/或亲和力决定了不同的表型 评价表达这些克隆型的B细胞的潜力。在 此外，自身反应性CD 4 + T细胞是否拯救了原发性应答B细胞 和/或促进记忆B细胞形成 将评估新自身HA。目标3将审查导致 器官特异性自身免疫的发展。一种自身免疫综合征， 类风湿性关节炎在TCRxHACII小鼠中发展，其中HA在 抗原呈递细胞，以及导致其 将对发展进行评估。病毒感染是否引起自身免疫， 表达低亲和力CD 4 + T细胞和/或CD 4 + T细胞的TCR xHACII小鼠 还将检查针对隐蔽的自身肽的方法。这些研究将 提供免疫耐受机制的基本见解，并将 直接关系到理解导致 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.