Toll Pathway & Control of Adaptive Immune Responses

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• 批准号: 8418750
• 负责人: Ruslan Medzhitov
• 金额: $ 38.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418750
• 关键词: Address; Antibody Formation; Antigens; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Dendritic Cells; Development; Disease; Family; Funding; Health; Host resistance; Immune response; Infection; Inflammatory; Interleukin-1; Interleukin-6; Knock-out; Ligands; Mediating; Molecular; Mus; Natural Immunity; Organism; Pathway interactions; Peripheral; Play; Process; Public Health; Receptor Activation; Receptor Signaling; Refractory; Regulation; Regulatory T-Lymphocyte; Resistance to infection; Role; Signal Pathway; Signal Transduction; T cell response; T-Cell Activation; T-Lymphocyte; Toll-like receptors; adaptive immunity; cell type; in vivo; microbial; prevent; receptor; receptor function; response; sensor

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) function as critical sensors of microbial infection. Upon recognition of microbial ligands, TLRs induce innate immune responses that are critical for host resistance against many types of microbial infections. In addition, TLRs induce dendritic cell maturation and activation of adaptive immune responses. We have previously characterized several aspects of TLR-mediated control of adaptive immunity. In the current application, we propose to investigate the cell type specific functions of TLRs and the IL-1 family receptors in vivo using conditional deletion of MyD88 in several cell types. We will investigate the role of TLR signaling in various cell types in innate resistance to infection and in the induction of adaptive immune responses. We will examine in detail TLR-dependent and TLR-independent mechanisms of B cell activation for antibody production. We will investigate the mechanisms whereby TLR induced signals block the induction of peripheral T cell tolerance, and the functional and mechanistic connection between these signals and suppression of T cell responses by regulatory T cells. Specifically, we will characterize the role of IL-6 signaling in T cells in the regulation of T cell activation and differentiation and suppression by regulatory T cells.

描述（由申请人提供）：Toll样受体（TLR）作为微生物感染的关键传感器。在识别微生物配体后，TLR会诱导先天免疫反应，这对于宿主对许多类型的微生物感染至关重要。另外，TLR诱导树突状细胞的成熟和适应性免疫反应的激活。我们先前已经表征了TLR介导的自适应免疫控制的几个方面。在当前应用中，我们建议在几种细胞类型中使用MyD88的条件缺失研究TLR和IL-1家族受体的细胞类型特异性功能。我们将研究TLR信号在各种细胞类型中的作用在对感染的先天抗性以及自适应免疫反应的诱导中的作用。我们将详细检查抗体生产的B细胞活化的TLR依赖性和TLR独立的机制。我们将研究TLR诱导信号阻止周围T细胞耐受性的诱导以及这些信号之间的功能和机械连接的机制，并通过调节性T细胞抑制T细胞反应。具体而言，我们将表征IL-6信号在T细胞中T细胞激活以及调节T细胞抑制的调节中的作用。

项目成果

Evolution of inflammatory diseases.

• DOI: 10.1016/j.cub.2012.07.029
• 发表时间: 2012-09-11
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Okin, Daniel;Medzhitov, Ruslan
• 通讯作者: Medzhitov, Ruslan

Bee venom phospholipase A2 induces a primary type 2 response that is dependent on the receptor ST2 and confers protective immunity.

• DOI: 10.1016/j.immuni.2013.10.006
• 发表时间: 2013-11-14
• 期刊: IMMUNITY
• 影响因子: 32.4
• 作者: Palm, Noah W.;Rosenstein, Rachel K.;Yu, Shuang;Schenten, Dominik D.;Florsheim, Esther;Medzhitov, Ruslan
• 通讯作者: Medzhitov, Ruslan

Role of basophils in the initiation of Th2 responses.

• DOI: 10.1016/j.coi.2010.01.012
• 发表时间: 2010-02
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Sokol CL;Medzhitov R
• 通讯作者: Medzhitov R

MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity.

• DOI: 10.1016/j.cmet.2009.08.013
• 发表时间: 2009-10
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Kleinridders A;Schenten D;Könner AC;Belgardt BF;Mauer J;Okamura T;Wunderlich FT;Medzhitov R;Brüning JC
• 通讯作者: Brüning JC

Regulation of adaptive immunity by the innate immune system.

• DOI: 10.1126/science.1183021
• 发表时间: 2010-01-15
• 期刊: Science (New York, N.Y.)
• 作者: Iwasaki A;Medzhitov R
• 通讯作者: Medzhitov R