CYTOLYTIC SYNAPSE · Regulation of cytotoxic T lymphocyte activity at the lytic synapse
6РП — Действия „Мария Кюри“
- Период
- 2006-02-01 → 2010-01-31
- Финансиране от ЕС
- 1 444 600 €
- Участници
- 1
- Схема
- EIF
Линиите свързват координатора с партньорите. За проекти отпреди 2014 г. CORDIS не винаги дава точни координати. Тези точки са на ниво град или държава.
Накратко на български
Цитотоксичните Т-лимфоцити унищожават вирусни и туморни клетки чрез специална структура, наречена имунологична синапса. Разбирането на този процес и ролята на протеина WASP помага при разработването на генна терапия за синдрома на Вискот-Олдрич и борбата с раковите клетки.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - CYTOLYTIC SYNAPSE (Regulation of cytotoxic T lymphocyte activity at the lytic synapse)
The EXT project CYTOLYTIC SYNAPSE focused mainly on the study of cytolytic T lymphocytes (CTL), as central players of our immune system. Upon recognition of a specific antigen, CTL can directly kill virus-infected cells and tumour cells by delivering lytic granules at the immunological synapse (IS), a structure corresponding to a 'cellular kiss'. Our main objective was to better define how the remodelling of actin (thin filaments making up the cytoskeleton) regulates the interaction between CTL and target cells at the IS. For that purpose, we studied CTL from Wiskott-Aldrich syndrome (WAS) patients as 'natural models'. Indeed, WAS is a life-threatening primary immunodeficiency caused by mutations in the gene encoding WASP, a key actin regulator in immune cells. Each researcher within the Team (1 early-stage researcher and 3 experienced researchers) was in charge of a specific project. The main scientific achievements obtained are the following: WASP regulates the molecular organisation and the stability of the IS; WASP regulates CTL cytotoxic activity, in particular against tumoural B cells ; tumoural B cells activate an abnormal actin remodelling program to regulate their motility. In addition, we provide a novel analytical method to study lytic granule composition and contribute to the preclinical validation of gene therapy for WAS. This project illustrates how the study of a rare disease as a model can yield data that are relevant way beyond the specific disease studied. Indeed, the study of a WAS patient with a secondary mutation was instructive in that it represents a case of 'natural gene therapy'. Our expertise on molecular regulation of actin cytoskeleton remodelling in lymphocytes from WAS patients was used to investigate how malignant lymphocytes remodel their actin cytoskeleton as a 'strategy' to migrate and invade tissues.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The lytic activity of cytotoxic T lymphocytes (CTL) plays a central role in the control of viral infection, cancer and homeostasis. The lethal hit of CTL is delivered to the target cell at the level of a highly organized synaptic structure (lytic synapse). How composition and organization of the lytic synapse contribute to the regulation of the lytic activity is largely unknown. The focus of this proposal is to study the lytic synapse of CTL isolated from patients affected by life-threatening primary immuno deficiencies (PID). CTL from patients with genetic mutations causing defects in cytolytic activity are unique natural knock-out models. The following PID will be considered: 1) Wiskott-Aldrich Syndrome due to WASP deficiency, 2) X-linked Lympho-Proliferati ve disease due to SAP deficiency, 3) Familial Hemophagocytic Lymphohistiocytosis due to perforin deficiency. This project will investigate the dynamics of molecular events that occur at the lytic synapse formed between CTL and antigen-loaded antigen-presen ting cells, using time-lapse video recording of the distribution of receptors and signalling components. Analysis of CTL activation and lytic activity will be performed in parallel. These approaches will be combined to lentiviral vector-mediated transfer o f untagged or GFP-tagged constructs encoding WASP, SAP and perforin, in order to visualize these proteins and to correct the lytic function of CTL from PID patients. In addition, a proteomics approach will be employed to identify novel proteins in healthy CTL that could complete our understanding of the lytic synapse architecture and function. This project will provide new insights in the mechanisms regulating CTL activity and in the physiopathology of severe PID. In addition, it will be instrumental for th e development of gene therapy for these severe PID and will have implications for the design of novel therapeutic approaches in which CTL mediated immunosurveillance plays a crucial role.
Оригинален текст от CORDIS (на английски).
Участници
- INSTITUT NATIONAL DE LA SANTÇ ET DE LA RECHERCHE MÈICALE · PARISКоординаторНиво градФранция
Връзки
Данни: CORDIS, © Европейски съюз