Regulation of memory T cell trafficking by core 2 O-glycan synthesis

项目摘要/摘要 经历过抗原的记忆T细胞构成了一种多样化、异质性的免疫细胞群体，即 在一生中对各种病原体、疫苗、过敏原、自身抗原和其他 环境因素。事实上，随着我们年龄的增长，新的幼稚T细胞的生成会减少，记忆T细胞 人口在剧目中占据主导地位。因此，调节多种功能的基本机制 记忆T细胞群与各种疾病和病理状况有广泛的相关性，包括 疫苗设计、免疫治疗方案以及炎症性或自身免疫性疾病的治疗或预防 精神错乱。尽管循环中记忆性CD8和CD4T细胞的形成和分化 已被广泛表征，记忆T细胞主动归宿和渗透组织的能力 它们展示了它们的效应器功能，人们对此知之甚少。我们最近发现记忆CD8 T细胞 需要翻译后选择素配体的O-连接糖基化才能运输和渗透到非 淋巴组织。此外，我们还发现核糖链的从头合成仅限于 记忆T细胞，并可以以不依赖于抗原的方式进行调节。然而，基本的分子 记忆CD8和CD4T细胞核心O-糖链合成和转运的调节机制 感染的特征尚未完全确定。具体地说，我们将1)确定不同的CD8 T细胞群 有能力合成核心O-糖链并运输到非淋巴组织，2)定义分子 以及调节记忆性CD8 T细胞中核心20-糖链合成的转录机制，以及3) 确定记忆的CD4T细胞是否需要核心20-糖链的合成来运输到非淋巴组织 急性或慢性病毒感染。因此，我们研究的总体目标将是确定和描述 调节不同记忆T细胞群运输的机制以及如何加强这一点 (用于宿主保护)或抑制(用于过敏或自身免疫)。

PROJECT SUMMARY/ABSTRACT Antigen-experienced memory T cells constitute a diverse, heterogeneous population of immune cells that is generated throughout life in response to a variety of pathogens, vaccines, allergens, self-antigens and other environment factors. In fact, as we age, generation of new naïve T cells diminishes and memory T cell populations dominate the repertoire. Thus, the basic mechanisms that regulate the functions of diverse memory T cell populations has broad relevance for a variety of diseases and pathological conditions including vaccine designs, immunotherapy protocols and treatment or prevention of inflammatory or autoimmune disorders. Although the formation and differentiation of memory CD8+ and CD4+ T cells in the circulation has been extensively characterized, the capacity for memory T cells to actively home to and infiltrate tissues where they exhibit their effector functions is less understood. We have recently discovered that memory CD8+ T cells require post-translational O-linked glycosylation of selectin ligands for trafficking to and infiltrating non- lymphoid tissues. Furthermore, we identified that de novo synthesis of core 2 O-glycans is restricted to memory T cells and can be regulated in an antigen-independent manner. However, the basic molecular mechanisms regulating core 2 O-glycan synthesis and trafficking of memory CD8+ and CD4+ T cells during infections are yet to be fully characterized. Specifically, we will 1) determine if different CD8+ T cell populations have the capacity to synthesize core 2 O-glycans and traffic into non-lymphoid tissues, 2) define the molecular and transcriptional mechanisms that regulate core 2 O-glycan synthesis in memory CD8+ T cells, and 3) determine if memory CD4+ T cells require core 2 O-glycan synthesis to traffic into non-lymphoid tissues during either acute or chronic viral infections. Thus, the overall goal of our study will be to identify and characterize the mechanisms regulating the trafficking of diverse memory T cell populations and how this can be enhanced (for host protection) or inhibited (for allergies or autoimmunity).