LY49-AUTOIMMUNITY · Regulation of immune responses and autoimmunity by activating and inhibitory NK receptors expressed by T lymphocytes: role of ITAM versus ITIM signal balance
6РП — Действия „Мария Кюри“
- Период
- 2006-05-01 → 2008-04-30
- Финансиране от ЕС
- 183 456 €
- 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
Т-лимфоцитите понякога придобиват рецептори на NK клетките (например Ly49D), което им позволява да атакуват цели независимо от обичайните си механизми за разпознаване. Това помага да се разбере защо при някои автоимунни заболявания и хронични възпаления имунната система атакува собствените тъкани неконтролируемо.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - LY49-AUTOIMMUNITY (Regulation of immune responses and autoimmunity by activating and inhibitory NK receptors expressed by T lymphocytes ...)
In the immune system, the balance between activating signals (i.e. ITAM receptors) and inhibitory signals (i.e. ITIM receptors) normally gives rise to an adequate and fine-tuned response against pathogens. Thus, the response of the effector killing cells can be modulated, to avoid a too long or too strong response that may be deleterious for the organism. This balance through ITAM and ITIM receptors is important for the biology of NK cells, the killer cells of innate immunity. Recent studies have shown that some activating NK receptors (ITAM receptor) can be expressed by T cells particularly in case of chronic inflammatory disorders or autoimmunity. To analyse if expression of NK ITAM-receptors can remove some specificity to the adaptive immunity, we used a mouse model, which aberrantly express a NK ITAM-receptor Ly49D on their T cells. In this project, we could determine that engagement of Ly49D on T cells triggers a wide range of activities, normally restricted to TCR engagement (TCR is the classical activating receptor of T cells). The T cells are able to produce inflammatory soluble factors, to survive and to proliferate. Most importantly, Ly49D expressing T cells can kill tumour cells that express the ligand recognised by Ly49D in vitro and in vivo. Thus T cells expressing activating NK receptors (receptors from the innate arm of the immune system) acquire a new autonomous activation system, totally independent of the specificity of the TCR, losing partially their features of cells from the adaptive immune system. The results generated in our study can partially explain the uncontrolled killing function of T cells in chronic inflammatory disorders or autoimmunity, because of the loss of TCR specificity. In addition, we demonstrate that activating NK receptors expressed by T cells can be used to enhance killing in an immunotherapy strategy against cancer.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Immune cell activity is regulated by both activating and inhibitory receptors, which transduce signals through two motifs: ITAM and ITIM, respectively. ITIM receptors play a key role in the regulation of ITAM induced activation of leukocytes, thus creating a balance, which regulates cellular functions and the outcome of the immune response (immune priming or tolerance).Moreover aberrant expression of activating and/or inhibitory immune receptors and of their ligands can lead to deleterious effects, including autoimmunity. While inhibitory NK receptors are also often expressed by normal T cells, the activating counterparts are mostly found on pathogenic self reactive T cells in autoimmune diseases.Transgenic mice expressing activating receptor Ly49D/DAP12 an d/or its inhibitory counterpart Ly49A (in presence/absence of H 2Dd as ligand) offer the opportunity to better understand the role of ITAM/ITIM balance in T cell biology, and the relevance of T cell ITAM signalling (via DAP12) in autoimmunity.We first pro pose to address T lymphocyte differentiation in Ly49D/DAP12 transgenic mice, by studying thymocyte development and TCR repertoire selection. Peripheral T lymphocyte function will be investigated upon Ly49D engagement alone or in combination with TCR stimulation.With the aim to assess the function of activating receptors expressed by CD8+ T cells in autoimmunity, a model of diabetes will be used (RIP-LCMV mice). The CD8+ T cells of the Ly49D/DAP12 transgenic mice will be will be transferred into RIP LCMV G P transgenic mice, whose beta islet cells express LCMV GP (lymphocytic choriomeningitis glycoprotein) as self antigen.In this model, self-reactive CD8+ T cells trigger diabetes only upon adequate stimulation (e.g. LMCV infection, CD28/B7.2 costimulation). We will test whether ITAM signalling via Ly49D/DAP12 is sufficient to trigger diabetes. Consequently this approach might allow bringing new insight in autoimmunity to design novel appropriate treatments.
Оригинален текст от CORDIS (на английски).
Участници
- LUDWIG INSTITUTE FOR CANCER RESEARCH, LAUSANNE BRANCH · EPALINGESКоординаторНиво градШвейцария
Връзки
Данни: CORDIS, © Европейски съюз