Regulatory T Cell Activity in Anti-Viral Immunity

有强有力的证据表明，CD4+CD25+Foxp3+调节性T细胞(Treg)是在胸腺内产生的 对自体多肽的反应。然而，Treg细胞也会改变对感染性病原体的免疫反应，以及自体多肽如何- 特异性Treg细胞可以识别和修饰包括B和T在内的抗病原体免疫反应 细胞记忆的形成，目前尚不清楚。在初步研究中，我们发现Treg细胞是 当流感病毒血凝素表达为自身抗原时，根据其对流感病毒血凝素的特异性产生 在转基因小鼠中可以调节对流感病毒的免疫反应。该项目将测试 假设基于自身多肽的特异性而产生的Treg细胞可以调节 交叉反应病毒多肽激活后细菌对流感病毒的免疫反应 多肽，或感染部位的自体多肽。目标1将确定这种Treg细胞活动如何影响 抗流感病毒免疫。Treg细胞调节保护性抗体形成的能力 接种流感病毒疫苗后的反应，以及它们的活性如何影响病毒清除、抗病毒 由流感病毒感染引起的免疫以及炎症和组织损伤将是 评估过了。目的2将确定感染如何改变Treg细胞的表达和活性。 流感病毒感染是否会导致Treg细胞库的短期或长期变化，以及 流感病毒感染后Treg细胞的激活程度可以改变免疫反应 将检查并发或随后的细菌感染(或反之亦然)。目标3将决定如何 病毒和/或自身多肽的TCR特异性可以在感染宿主中引导Treg细胞的活性。是否激活 弱交叉反应病毒多肽对自身多肽特异性Treg细胞的免疫调节作用 将检查流感病毒感染情况，以及自体多肽激活Treg细胞的能力，以修改 将评估对流感病毒感染的免疫反应。长期目标是确定是否 以及如何改变Treg细胞的活性以加强疫苗接种和/或限制发病率和死亡率 由流感病毒感染引起。

There is strong evidence that CD4+CD25+Foxp3+ regulatory T (Treg) cells are generated intrathymically in response to self-peptides. Yet, Treg cells also modify immune responses to infectious agents, and how selfpeptide- specific Treg cells can recognize and modify anti-pathogen immune responses, including B and T cell memory formation, is currently unknown. In preliminary studies we have found that Treg cells that are generated based on their specificity for the influenza virus hemagglutinin when it is expressed as a selfantigen in transgenic mice can modulate immune responses to influenza virus. This project will test the hypothesis that Treg cells that have been generated based on specificity for self-peptides can modulate immune responses to influenza virus following activation by crossreactive viral peptides, by bacterial peptides, or by self-peptides at the site of infection. Aim 1 will determine how such Treg cell activity impacts anti-influenza virus immunity. The ability of Treg cells to modulate the development of protective antibody responses following influenza virus vaccination, and how their activity can affect virus clearance, anti-viral immunity and the inflammation and tissue damage that are induced by influenza virus infection will be assessed. Aim 2 will determine how infection can modify the representation and activity of Treg cells. Whether influenza virus infection induces short- or long-term changes in the Treg cell repertoire, and the extent to which Treg cell activation in response to influenza virus infection can alter the immune response to a concurrent or subsequent bacterial infection (or vice versa) will be examined. Aim 3 will determine how TCR specificity for viral and/or self-peptides can guide Treg cell activity in infected hosts. Whether activation of self-peptide-specific Treg cells by weakly crossreactive viral peptides can modify the immune response to influenza virus infection will be examined, and the ability of self-peptides to activate Treg cells to modify the immune response to influenza virus infection will be assessed. The long-term goal is to determine whether and how Treg cell activity might be modified to enhance vaccination and/or limit the morbidity and mortality caused by influenza virus infection.