H2020Индивидуална стипендия2015–2017

IMSTREV · Immune modulation by lymph node stromal cell-derived extracellular vesicles

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2015-07-01 → 2017-06-30
Финансиране от ЕС: 171 461 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Молекулите, отделяни от стромални клетки в лимфните възли на червата, регулират работата на имунната система. Разбирането на тези механизми помага при разработването на нови ваксини и при изучаването на хронични възпалителни заболявания.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Immune modulation by lymph node stromal cell-derived extracellular vesicles

The problem/issue being addressed and overall objectives The gut mucosa represents the largest and most dynamic immunological environment, where immune cells continuously traffic and reside. Their major role is to clear harmful pathogens and to maintain tolerance against harmless commensal bacteria and food antigens. Regulatory T cells (Tregs), endowed with immune suppressive capacity, are the master regulators of mucosal tolerance. Therefore, they have attracted an increasing interest as potential therapeutic targets in chronic inflammatory diseases, such as ulcerative colitis or inflammatory bowel disease. The aim of the proposal was to better understand the mechanism of peripheral tolerance, and based on previous observations showing that the gut‑draining mesenteric lymph nodes (mLN) harbor superior Treg‑inducing capacity (Cording, Muc Immunol, 2014), which could be attributed to LN stromal cells, namely to fibroblastic reticular cells (FRCs). My goals included: - the identification of tolerogenic molecules secreted from mLN FRCs, - to reveal their intercellular transfer via FRC-derived microvesicles (MVs), - and to understand the crosstalk between FRCs and dendritic cells (DCs) under tolerogenic circumstances. Importance for the society Gaining insight into the molecular mechanisms of peripheral tolerance can pave the way for future vaccine developments by identifying promising targets. Furthermore, my continuous interaction with researchers during conferences, inside my host institution, with my previous laboratory in Hungary and my future laboratory in Munich expands the cooperation between countries of the European Union. Conclusion of the action The results can be divided into two major parts, because the work plan was revised at the end of the first year (reported to the project organizer on 09-05-2016). 1. The tumor growth factor‑β1 (TGF‑β1) cytokine, known to play critical role in driving Treg differentiation, was upregulated in mLN-iFRCs, was associated with mLN-iFRC-derived MVs, and was shown as one of the major mediators of their Treg induction. These results have been accepted for publication at the European Journal of Immunology. 2. Resident DCs from the mLN were shown to harbor tolerogenic gene signatures and moderate Treg‑inducing capacity, which was stably maintained after transplantation to the skin-draining site, and suggests its imprinting driven by mLN-FRCs. I am aiming to publish these data in a high-impact scientific journal as a separate manuscript.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Regulatory T cells (Tregs) are essential for maintenance of immune homeostasis and peripheral tolerance. The unique challenge to discriminate between pathogens and commensals requires the dynamic adaptation of Tregs to the microenvironment, particularly in the intestinal mucosa. Accordingly, although Tregs are primarily generated in the thymus, they can be also generated in the periphery, and gut-draining mesenteric lymph nodes (mLN) were shown to display a higher Treg-inducing capacity compared to skin-draining peripheral LNs (pLN).Our previous data suggest that these site-specific functional differences of LNs can be attributed to fibroblastic reticular stromal cells (FRCs), and the high Treg-inducing capacity of mLN can be imprinted in LN stromal cells by commensal microbiota. To decipher the molecular details of these site-specific immune-modulatory differences we generated immortalized FRCs, and preliminary data suggest that soluble factors secreted by mLN-derived FRCs mediate the high Treg-inducing capacity of mLN.The present proposal aims to identify molecules secreted from mLN-FRCs that modulate the differentiation of naïve T cells into Tregs. Special emphasis will be laid on the novel field of intercellular communication by extracellular vesicles (EVs), and both RNA-Seq and mass spectrometry approaches will be applied to identify the critical factors on a molecular level. To formally proof the functional importance of the newly identified candidate molecules, immortalized FRCs will be genome-edited using CRISPR-Cas9 technology and tested for their Treg-inducing capacity.Gaining insight into the cellular-subcellular interactions and major molecular mechanisms of peripheral tolerance and Treg generation anticipates promising tools for future vaccine development and therapeutic applications to treat chronic inflammatory and autoimmune diseases.

Оригинален текст от CORDIS (на английски).

Участници

HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH · BraunschweigКоординаторГермания