Toll-like receptor mediated regulation of effector and memory CD4 T cell response

描述（由申请人提供）：Toll样受体（TLR）是模式识别受体（PRR）家族，其识别来自不同类别微生物的多种病原体相关分子模式（PAMP），并在宿主的先天免疫防御中发挥重要作用。此外，TLR已显示在诱导适应性免疫应答中起关键作用。树突状细胞（DC）上TLR对PAMP的识别导致DC成熟，这是一个涉及MHC和共刺激分子表达增强以及迁移至引流淋巴结以引发初始T细胞的过程。TLR活化还导致促炎细胞因子的产生，其通过克服Treg介导的抑制而有助于CD 4 T细胞活化。值得注意的是，TLR表达不限于DC。除了骨髓来源的细胞如DC和巨噬细胞之外，其他细胞如嗜中性粒细胞、上皮细胞、成纤维细胞、B淋巴细胞和T淋巴细胞已显示表达功能性TLR。虽然TLR活化在所有这些细胞类型中的结果是相当不同的，但它们对初始CD 4 T细胞活化的单独贡献还没有很好地理解。本研究的总体目标是表征TLR依赖性机制，其控制幼稚CD 4 T细胞的活化及其分化为长寿记忆细胞。提出了三个具体的目标来研究TLR在控制适应性免疫中的作用。目的1将表征不同TLR表达细胞在初始CD 4 T细胞活化中的作用。目的2分析DC分泌的细胞因子，特别是IL-1和IL-6对体内CD 4 T细胞活化的作用。目的3提出了解TLR激活DC有助于产生CD 4 T细胞记忆的机制。总之，这些研究将产生新的见解如何识别病原体通过TLR形状的CD 4 T细胞反应，并将导致更好地了解先天控制的适应性免疫反应在体内的机制。此外，这项工作将有助于设计有效的疫苗配方，用于预防接种。

DESCRIPTION (provided by applicant): The Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that recognize a diverse set of Pathogen Associated Molecular Patterns (PAMPs) from different classes of microbes and play an essential role in innate immune defense of the host. In addition, TLRs have been shown to play a critical role in induction of adaptive immune responses. Recognition of PAMPs by TLRs on dendritic cells (DCs) leads to DC maturation, a process that involves enhanced expression of MHC and co-stimulatory molecules as well as migration to the draining lymph nodes to prime naive T cells. TLR activation also leads to production of pro-inflammatory cytokines that contribute to CD4 T cell activation by overcoming Treg mediated suppression. Notably, TLR expression is not limited to DCs. In addition to cells of myeloid origin such as DCs and macrophages, other cells such as neutrophils, epithelial cells, fibroblasts, B lymphocytes and T lymphocytes have been shown to express functional TLRs. Although the outcome of TLR activation in all of these cell types is quite different, their individual contribution to the activation of naive CD4 T cells is not well understood. The overall goals of this study are to characterize TLR dependent mechanisms that control activation of naive CD4 T cells and their differentiation into long lived memory cells. Three specific aims are proposed to study the role of TLRs in controlling adaptive immunity. Aim 1 will characterize the role of different TLR expressing cells in naive CD4 T cell activation. Aim 2 will analyze the contribution of cytokines secreted by DCs, particularly Interleukin-1 and Interleukin-6, to CD4 T cell activation in vivo. Aim 3 proposes to understand the mechanisms by which TLR activation of DCs contributes to generation of CD4 T cell memory. Together these studies will yield novel insights into how recognition of pathogens via TLRs shapes CD4 T cell responses and will lead to better understanding of the mechanisms of innate control of adaptive immune responses in vivo. Furthermore, this work will aid in designing effective vaccine formulations for prophylactic vaccinations.