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（TLRs）是一种模式识别受体（PRRs）家族，可识别来自不同类别微生物的多种病原体相关分子模式（Pathogen Associated Molecular Patterns, PAMPs），并在宿主的先天免疫防御中发挥重要作用。此外，tlr已被证明在诱导适应性免疫反应中发挥关键作用。树突状细胞（DC）上TLRs对PAMPs的识别导致DC成熟，这一过程包括MHC和共刺激分子的表达增强，以及向引流淋巴结迁移到初始初始T细胞。TLR激活还导致促炎细胞因子的产生，通过克服Treg介导的抑制，促进CD4 T细胞活化。值得注意的是，TLR的表达并不局限于dc。除了髓系细胞如DCs和巨噬细胞外，其他细胞如中性粒细胞、上皮细胞、成纤维细胞、B淋巴细胞和T淋巴细胞已被证明表达功能性tlr。尽管TLR在所有这些细胞类型中激活的结果是完全不同的，但它们对初始CD4 T细胞激活的个体贡献尚不清楚。本研究的总体目标是表征TLR依赖的机制，该机制控制初始CD4 T细胞的激活并将其分化为长寿的记忆细胞。研究tlr在控制适应性免疫中的作用有三个具体目的。目的1将描述不同TLR表达细胞在初始CD4 T细胞活化中的作用。Aim 2将分析dc分泌的细胞因子，特别是白细胞介素-1和白细胞介素-6对体内CD4 T细胞活化的贡献。目的3旨在了解TLR激活dc有助于产生CD4 T细胞记忆的机制。总之，这些研究将对通过tlr识别病原体如何影响CD4 T细胞反应产生新的见解，并将更好地理解体内适应性免疫反应的先天控制机制。此外，这项工作将有助于为预防性接种设计有效的疫苗配方。

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.