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

描述（由申请方提供）：吞噬细胞对垂死细胞的清除通常被认为是一种非炎症或耐受性过程。流行的观点是，由正常组织更新产生的凋亡细胞被迁移到局部淋巴结的DC捕获，在那里它们诱导T细胞耐受、T细胞无反应性或T细胞缺失。然而，DC对凋亡细胞的吞噬作用也可以具有促炎作用，其与细胞相关的自身抗原向T细胞的呈递结合可以导致自身特异性T细胞的增加。支配耐受性和促炎性T细胞应答的诱导之间的决定的机制不仅与我们对自身免疫性疾病的发展和进展的理解相关，而且对于移植和肿瘤细胞疫苗接种领域也是至关重要的，这些领域都涉及细胞死亡和对细胞相关抗原的自反应性T细胞的诱导。目前的研究表明，免疫抑制和促炎反应之间的平衡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极大影响。我们最近鉴定了一种新的DC亚群，nDC CD 11 c + CD 11b-CD 4-CD 81-，与其他交叉呈递DC亚群相比，其有效地（交叉）引发CD 4+和CD 8 + T细胞与细胞相关抗原。该nDC亚群在摄取在T细胞引发中充当佐剂的凋亡物质后产生I型IFN。由这些nDC引发的CD 8 +T细胞不会变得耐受或无反应性，但显示增强的初级克隆扩增，并在每个细胞基础上产生更多的细胞因子/效应分子。此外，由nDC引发的CD 8 +T细胞在体内和体外显示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）如何引发的nDC影响CD 8 + T细胞的指导程序，和（ii）如何在收购凋亡材料后的nDC的I型IFN生产影响CD 8 +T细胞的命运。树突状细胞（DC）对细胞相关抗原的交叉呈递通常导致T细胞耐受的诱导，但在某些情况下导致有效的T细胞引发。在这个项目中，我们将研究不同DC亚群如何呈递细胞相关抗原-来自垂死细胞-影响抗原特异性CD 8 +T细胞应答的表型和命运。

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.