T cell memory to cell-associated antigens by a new DC subset

新的 DC 亚群对细胞相关抗原的 T 细胞记忆

• 批准号: 7664436
• 负责人: Edith M Janssen
• 金额: $ 18.75万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664436
• 关键词: Adjuvant; Affect; Antigens; Apoptotic; Autoimmune Diseases; CD11c Antigens; CD8B1 gene; Cell Death Induction; Cells; Clonal Expansion; Cross Presentation; Cross-Priming; Data; Dendritic Cells; Development; Equilibrium; Goals; ITGAM gene; ITGAX gene; Immune; Immunization; In Vitro; Inflammatory; Inflammatory Response; Interferons; Lead; MHC Class I Genes; Memory; Mus; Nature; Normal tissue morphology; Pathway interactions; Phagocytes; Phagocytosis; Phenotype; Process; Production; Research; Role; Source; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; Transgenic Organisms; Transplantation; Vaccination; anergy; base; cell type; cytokine; in vivo; lymph nodes; neoplastic cell; novel; programs; public health relevance; receptor; response; uptake

DESCRIPTION (provided by applicant): Clearance of dying cells by phagocytes is generally considered to be a non-inflammatory or tolerizing process. The prevailing view is that apoptotic cells generated by normal tissue turnover are captured by DC that migrate to local lymph nodes, where they induce T cell tolerance, T cell anergy, or T cell deletion. However, phagocytosis of apoptotic cells by DC can also have pro-inflammatory effects, which in combination with the presentation of cell-associated auto-antigens to T cells- can lead to the rise of self-specific T cells. The mechanisms that govern the decision between the induction of tolerizing and pro-inflammatory T cell responses are not only relevant for our understanding of the development and progression of autoimmune disorders, but are also crucial for the fields of transplantation and tumor cell vaccination that all deal with cell- death and induction of self-reactive T cells to cell-associated antigens. Current research suggests that the balance between immune-suppressive and pro-inflammatory responses is greatly affected by the type of phagocytic cell that is involved and the milieu created by this phagocytosing cell. We recently identified a novel DC subset, nDC CD11c+CD11b-CD4-CD81-, that in contrast with other cross- presenting DC subsets potently (cross-)primes both CD4+ and CD8+ T cells to cell-associated antigens. This nDC subset produces type I IFNs after uptake of apoptotic material that acts as adjuvant in the priming of T cells. CD8+T cells primed by these nDC do not become tolerant or anergic, but display enhanced primary clonal expansion and produce more cytokine/effector molecules on a per cell base. In addition, CD8+T cells primed by nDC show greater capacity for secondary expansion and memory development in vivo and in vitro. In this study we seek to determine (i) how priming by nDC affects the instructional program in CD8+ T cells, and (ii) how type I IFN production by the nDC upon acquisition of apoptotic material affects CD8+T cell fate. PUBLIC HEALTH RELEVANCE Cross-presentation of cell-associated antigens by dendritic cells (DC) generally leads to the induction of T cell tolerance, but in some cases to potent T cell priming. In this project we will study how presentation of cell- associated antigens -derived from dying cells- by different DC subsets affects the phenotype and fate of antigen-specific CD8+T cell responses.

描述(申请人提供)：吞噬细胞清除死亡细胞通常被认为是一个非炎症性或耐受性的过程。流行的观点认为，正常组织更新产生的凋亡细胞被DC捕获，并迁移到局部淋巴结，在那里它们诱导T细胞耐受、T细胞无能或T细胞缺失。然而，DC对凋亡细胞的吞噬也可以起到促炎作用，与细胞相关的自身抗原呈递给T细胞-可以导致自身特异性T细胞的上升。在诱导耐受性和促炎性T细胞反应之间做出决定的机制不仅关系到我们对自身免疫性疾病的发展和进展的理解，而且对于移植和肿瘤细胞疫苗领域也是至关重要的，这些领域都涉及细胞死亡和诱导自身反应性T细胞产生细胞相关抗原。目前的研究表明，免疫抑制和促炎反应之间的平衡很大程度上受到所涉及的吞噬细胞类型和这种吞噬细胞所创造的环境的影响。我们最近发现了一种新的DC亚群，NDC CD11c+CD11b-CD4-CD81-，与其他交叉呈递的DC亚群相比，它能有效地(交叉)启动CD4+和CD8+T细胞对细胞相关抗原的反应。这个NDC亚群在摄取作为T细胞启动佐剂的凋亡物质后产生I型IFN。由这些NDC激活的CD8+T细胞不会变得耐受或无能，但会表现出增强的原代克隆性扩张，并在每个细胞基础上产生更多的细胞因子/效应分子。此外，经NDC激活的CD8+T细胞在体内和体外表现出更大的二次扩增和记忆发育能力。在这项研究中，我们试图确定(I)NDC如何启动CD8+T细胞的指导程序，以及(Ii)NDC在获得凋亡物质时产生的I型干扰素如何影响CD8+T细胞的命运。公共卫生相关性树突状细胞(DC)对细胞相关抗原的交叉提呈通常会导致T细胞耐受的诱导，但在某些情况下会导致有效的T细胞启动。在这个项目中，我们将研究不同DC亚群对细胞相关抗原(来源于死亡细胞)的呈递如何影响抗原特异性CD8+T细胞反应的表型和命运。