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

描述（由申请人提供）：吞噬细胞对死亡细胞的清除通常被认为是一个非炎症或耐受的过程。普遍的观点是，正常组织转换产生的凋亡细胞被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细胞能量或T细胞缺失。然而，DC对凋亡细胞的吞噬也可能具有促炎作用，这与细胞相关自身抗原向T细胞的呈递相结合，可导致自身特异性T细胞的增加。决定诱导耐受和促炎T细胞反应的机制不仅与我们对自身免疫性疾病的发生和进展的理解有关，而且对于移植和肿瘤细胞疫苗接种领域也至关重要，这些领域都涉及细胞死亡和诱导自身反应性T细胞对细胞相关抗原的反应。目前的研究表明，免疫抑制和促炎反应之间的平衡在很大程度上受到所涉及的吞噬细胞类型和吞噬细胞所产生的环境的影响。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亚群不同，它能有效地（交叉）将CD4+和CD8+ T细胞引到细胞相关抗原上。这个nDC亚群在摄取凋亡物质后产生I型ifn，在T细胞的启动中起辅助作用。由这些nDC引发的CD8+T细胞不会变得耐受或无能，但会表现出增强的原克隆扩增，并在每个细胞基础上产生更多的细胞因子/效应分子。此外，nDC诱导的CD8+T细胞在体内和体外均表现出更强的二次扩增和记忆发育能力。在本研究中，我们试图确定(i) nDC的启动如何影响CD8+T细胞中的指导程序，以及（ii） nDC在获得凋亡物质后产生的i型IFN如何影响CD8+T细胞的命运。树突状细胞（DC）交叉呈递细胞相关抗原通常会诱导T细胞耐受，但在某些情况下会诱导强效T细胞启动。在这个项目中，我们将研究细胞相关抗原-来源于死亡细胞-如何通过不同的DC亚群呈现影响抗原特异性CD8+T细胞反应的表型和命运。

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.