CD8DC FUNCTIONS · DNRG-1 as a marker to develop better models for characterising human and mouse dendritic subsets and for analysing their functional role in vivo
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2009-10-01 → 2011-09-30
- Финансиране от ЕС
- 180 784 €
- Участници
- 1
- Схема
- MC-IEF
Линиите свързват координатора с партньорите.
Накратко на български
Специфични дендритни клетки при хората (DNGR-1+ BDCA3hi) се анализират, за да се разбере как те разпознават чужди антигени и активират Т-клетките. Това помага за създаването на по-добри модели за имунотерапия и ваксини.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
DNRG-1 as a marker to develop better models for characterising human and mouse dendritic subsets and for analysing their functional role in vivo
In mouse, a subset of dendritic cells (DCs) known as CD8alpha+ DCs has emerged as an important player in the regulation of T cell responses and a promising target in vaccination strategies. However, translation into clinical protocols has been hampered by the failure to identify CD8alpha + DCs in humans. Here, we characterise a population of human DCs that expresses DNGR-1 (CLEC9A) and high levels of BDCA3 and resembles mouse CD8alpha + DCs in phenotype and function. We describe the presence of such cells in the spleens of humans and humanised mice and report on a protocol to generate them in vitro. Like mouse CD8alpha + DCs, human DNGR-1+ BDCA3hi DCs express Necl2, CD207, BATF3, IRF8, and TLR3, but not CD11b, IRF4, TLR7, or (unlike CD8alpha + DCs) TLR9. DNGR-1+ BDCA3hi DCs respond to polyI: C and agonists of TLR8, but not of TLR7, and produce interleukin (IL)-12 when given innate and T cell-derived signals. Notably, DNGR-1+ BDCA3+ DCs from in vitro cultures efficiently internalise material from dead cells and can cross-present exogenous antigens to CD8+ T cells upon treatment with poly I: C. The characterisation of human DNGR-1+ BDCA3hi DCs and the ability to grow them in vitro opens the door for exploiting this subset in immunotherapy.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The dendritic cell (DC) system of antigen-presenting cells controls immunity and tolerance. The unresolved issues on DC heterogeneity represent an important hurdle in the development of DC-based immunotherapies. The identification of the DNGR-1 marker by the host lab allows us to develop better models for characterising human and mouse DC. In the mouse, this marker is selectively expressed in mouse CD8+DC and then, we believe that it constitutes a better marker for CD8+DC in vivo and, therefore, will carry out a detailed analysis of the distribution of DNGR-1+ cells. We plan also to extend our work to imaging CD8+DC and their interactions in vivo with T and B cells, and other DC as langerhans cells. This aim will be achieved by using and constructing knock-in (KI) mice that express a green or red fluorescent protein specifiquely to tag the CD8+DC. The function of CD8+DC remains speculative, in part because of the lack of models in which only one DC subtype could present a given antigen to T cells. We aim to circumvent this limitation by restricting the ability to present a given antigen to the CD8+DC. They are also a lack of models in which DC subtypes can be selectively ablated. The host laboratory has constructed mice to deplete, transiently or constitutively the CD8+DC. This model will allows us to assess the effect of ablation of CD8+DC on the immune system. In humans, it has been argued that CD8+DC are not present but this could simply reflect the fact that they have been overlooked. The host lab showed that DNGR-1 is also expressed by a small subset of human blood, sharing markers with mouse CD8+DC. Then, we plan to characterise the functional properties of human DNGR-1+DC in detail and determine whether they match those expected from the study of murine CD8+DC. Based on our results, strategies that aim to define cancer immunotherapies could refine their approach, as our work will transpose mouse data to a better understanding of human DC.
Оригинален текст от CORDIS (на английски).
Участници
- CANCER RESEARCH UK LBG · LONDONКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз