Lipid bodies organelles and the cross-presentation of cell-associated antigens by MHC class I in phagocytic dendritic cells

吞噬树突状细胞中脂体细胞器和 I 类 MHC 交叉呈递细胞相关抗原

• 批准号: MR/K01241X/1
• 负责人: Pierre Guermonprez
• 金额: $ 51.97万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK01241X%2F1
• 关键词: Lipid; bodies; organelles; cross; presentation

Dendritic cells (DCs) are a specific cell type of the immune system. They act as sentinels able to warn T cells to get activated and to proliferate in case of danger. Once danger has gone, some T cell specific for the antigen keep on patrolling and they are termed as memory T cells. In case of antigen reencounter, they have the interesting ability to respond faster and better. Practically, this process of memorization is the basis of vaccination during which the immune system acquire the ability to respond faster and better to a given pathogen. We are studying the beginning of the process which is termed as "antigen cross-presentation to T cells". A specific population of DCs activates a family of T cells called CD8+ T cells that have the ability of kill antigen-bearing cells like cells infected by virus during viral infection, for instance. Antigen cross-presentation by DCs, in this case, takes place because DCs can eat (phagocytose) dead cells that carry antigens. After their meal, DCs digest dead cells and then sample antigens (peptide molecules) out of the dead cell body to present them on display molecules (called MHC class I) at their surface. CD8+ T cells see the association of peptides with MHC molecules at the surface of the DCs. The focus of our research is : what is happening during the digestion ? how the small antigen get extracted from the dead cell body that had been eaten by the DC ?We had already found an organelle dedicated to store fat (lipid bodies) that regulates antigen cross-presentation. We want to understand better how it work. This research grant intend to test the function of some genes that enable to enable cells to eat a little pieces of themselves to produce energy quickly in case of stress. This process is called autophagy and also target these lipid bodies. We wonder is autophagy may not regulate, perhaps through lipid bodies regulation, the digestion of dead cell bodies and the production of the peptide antigen-MHC class I complexes. To test this hypothesis, we are going to develop some mutant mice in which autophagy genes or some regulator of autophagy are inactivated into DCs. We will use these mice to analyse what autophagy is doing during the phagocytosis of dead cells and to determine if autophagy is important for the cross-presentation of antigens to CD8+ T cells.

树突状细胞（Dendritic cells，DC）是免疫系统的一种特殊细胞类型。它们充当哨兵，能够警告T细胞在遇到危险时被激活并增殖。一旦危险消失，一些对抗原有特异性的T细胞会继续巡逻，它们被称为记忆T细胞。在抗原再次相遇的情况下，它们具有更快更好地响应的有趣能力。实际上，这种记忆过程是接种疫苗的基础，在此期间，免疫系统获得了对给定病原体更快更好地做出反应的能力。我们正在研究这个过程的开始，这个过程被称为“抗原交叉呈递给T细胞”。DC的特定群体激活称为CD 8 + T细胞的T细胞家族，其具有杀死携带抗原的细胞的能力，例如在病毒感染期间被病毒感染的细胞。在这种情况下，DC的抗原交叉呈递发生，因为DC可以吃掉（吞噬）携带抗原的死细胞。用餐后，DC消化死细胞，然后从死细胞体中提取抗原（肽分子），并将其呈递到表面的展示分子（称为MHC I类）上。CD 8 + T细胞在DC表面看到肽与MHC分子的缔合。我们研究的重点是：消化过程中发生了什么？小抗原是如何从被DC吃掉的死细胞体中提取出来的？我们已经发现了一种专门储存脂肪（脂质体）的细胞器，它调节抗原的交叉呈递。我们想更好地了解它是如何工作的。这项研究资助旨在测试一些基因的功能，这些基因能够使细胞在压力下吃掉自己的一小部分以快速产生能量。这个过程被称为自噬，也靶向这些脂质体。我们想知道的是，自噬可能不调节，也许通过脂质体调节，消化死细胞体和肽抗原-MHC I类复合物的产生。为了验证这一假设，我们将培养一些突变小鼠，其中自噬基因或一些自噬调节因子被灭活为DC。我们将使用这些小鼠来分析自噬在吞噬死细胞过程中的作用，并确定自噬对于抗原向CD 8 + T细胞的交叉呈递是否重要。

项目成果

Intracellular Transport Routes for MHC I and Their Relevance for Antigen Cross-Presentation.

• DOI: 10.3389/fimmu.2015.00335
• 发表时间: 2015
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Adiko AC;Babdor J;Gutiérrez-Martínez E;Guermonprez P;Saveanu L
• 通讯作者: Saveanu L

The protein tyrosine phosphatase PTPN22 negatively regulates presentation of immune complex derived antigens.

• DOI: 10.1038/s41598-018-31179-x
• 发表时间: 2018-08-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Clarke F;Purvis HA;Sanchez-Blanco C;Gutiérrez-Martinez E;Cornish GH;Zamoyska R;Guermonprez P;Cope AP
• 通讯作者: Cope AP

Cross-Presentation of Cell-Associated Antigens by MHC Class I in Dendritic Cell Subsets.

• DOI: 10.3389/fimmu.2015.00363
• 发表时间: 2015
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Gutiérrez-Martínez E;Planès R;Anselmi G;Reynolds M;Menezes S;Adiko AC;Saveanu L;Guermonprez P
• 通讯作者: Guermonprez P

Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection.

• DOI: 10.1038/ncomms14642
• 发表时间: 2017-03-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Péan CB;Schiebler M;Tan SW;Sharrock JA;Kierdorf K;Brown KP;Maserumule MC;Menezes S;Pilátová M;Bronda K;Guermonprez P;Stramer BM;Andres Floto R;Dionne MS
• 通讯作者: Dionne MS

Protein tyrosine phosphatase PTPN22 is dispensable for dendritic cell antigen processing and promotion of T-cell activation by dendritic cells.

• DOI: 10.1371/journal.pone.0186625
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Clarke F;Jordan CK;Gutiérrez-Martinez E;Bibby JA;Sanchez-Blanco C;Cornish GH;Dai X;Rawlings DJ;Zamoyska R;Guermonprez P;Cope AP;Purvis HA
• 通讯作者: Purvis HA