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

描述(申请人提供)：Toll样受体(TLRs)是一个模式识别受体(PRRs)家族，识别来自不同类别微生物的一组不同的病原体相关分子模式(PAMPs)，在宿主的先天性免疫防御中发挥重要作用。此外，TLRs已被证明在诱导获得性免疫反应中发挥关键作用。树突状细胞(DC)上的TLRs识别PAMPs导致DC成熟，这一过程包括增强MHC和共刺激分子的表达，以及迁移到引流淋巴结以激活初始T细胞。TLR的激活还导致促炎细胞因子的产生，这些细胞因子通过克服Treg介导的抑制而有助于CD4T细胞的激活。值得注意的是，TLR的表达并不局限于DC。除了DC和巨噬细胞等髓系来源的细胞外，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淋巴细胞也表达功能性TLRs。尽管TLR在所有这些细胞类型中的激活结果有很大的不同，但它们对初始CD4T细胞激活的单独贡献还没有被很好地理解。这项研究的总体目标是表征TLR依赖的机制，这些机制控制初始的CD4T细胞的激活和它们向长期记忆细胞的分化。为了研究TLRs在控制获得性免疫中的作用，提出了三个具体的目标。目的1研究不同TLR表达细胞在初始CD4T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在体内对CD4T细胞活化的作用。目的3旨在了解树突状细胞TLR激活促进CD4T细胞记忆产生的机制。总之，这些研究将对通过TLRs识别病原体如何塑造CD4T细胞反应产生新的见解，并将有助于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疫苗设计有效的疫苗配方。 公共卫生相关性：人类和其他多细胞生物体暴露于各种不同的病原体。免疫系统有专门的受体，称为Toll样受体(TLRs)，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立即防御宿主很重要。然而，防止再次感染的长期保护需要病原体特异性T细胞的激活。已有研究表明，T细胞的激活依赖于先天免疫系统细胞上TLRs的激活，即树突状细胞。在这个方案中，我们将研究树突状细胞中TLR激活有助于诱导T细胞的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新的针对病原体的疫苗接种策略。

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