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.
