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。 公共卫生相关性：人类和其他多细胞生物暴露于各种不同的病原体。免疫系统具有称为Toll样受体（TLR）的专门受体，以识别病原微生物的结构和代谢成分。这种识别对于先天免疫系统对宿主的立即防御是重要的。然而，长期防止再感染需要激活病原体特异性T细胞。已经显示T细胞活化依赖于先天免疫系统细胞（即树突细胞）上TLR的先前活化。在这个提议中，我们将研究树突状细胞中TLR激活有助于T细胞诱导长期保护性免疫的机制。从这些研究中获得的知识将有助于开发针对病原体的新疫苗接种策略

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. PUBLIC HEALTH RELEVANCE: Humans and other multicellular organisms are exposed to a wide variety of different pathogens. The immune system has specialized receptors called Toll-like receptors (TLRs) to recognize structural and metabolic components of pathogenic microbes. This recognition is important for immediate defense of the host by the innate immune system. Long-term protection from re-infection however requires activation of pathogen specific T cells. T cell activation has been shown to be dependent on prior activation of TLRs on the cells of the innate immune system, namely dendritic cells. In this proposal, we will study the mechanisms by which TLR activation in dendritic cells contributes to induction of long- term protective immunity by T cells. The knowledge acquired from these studies will aid in development of new vaccination strategies against pathogens