Wspólnotowy Serwis Informacyjny Badan i Rozwoju - CORDIS


TRIPOD Streszczenie raportu

Project ID: 322856
Źródło dofinansowania: FP7-IDEAS-ERC
Kraj: France

Mid-Term Report Summary - TRIPOD (Deciphering the regulatory T cell repertoire: towards biomarkers and biotherapies for autoimmune diseases)

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis and preventing autoimmune disorders. We showed that Tregs are composed of two major subsets (Fisson et al, 2003): CD44lo/-CD62Lhi naïve Tregs (nTregs) and CD44HiCD62Llo/- activated/memory Tregs (amTregs). nTregs are mainly quiescent and recirculating cells, while amTregs are highly proliferative, prominent in organ draining lymph nodes and enriched in self-antigen specific T cells (Fisson et al, 2003; Darrasse-Jèze et al, 2009; Chen et al, 2013). To further understand the biology of Tregs, it is critical to better understand their specificity, which is coded by their T cell receptor (TCR).
NGS sequencing now permits to analyse the extremely diverse TCR repertoire. Our preliminary study suggested major differences in TCR repertoire composition and diversity between nTregs and amTregs, as well as between brachial lymph node (LN) and pancreatic LN (LNs draining superficial tissues or a deep organ, respectively) (Bergot et al. 2015). This suggested an antigen-driven compartmentalisation of Tregs across the body.
Understanding distribution of Treg specificity in time and space is thus of utmost importance in order to better understand autoimmune diseases development and outcome, and develop new therapeutic methods based on antigen specific Tregs.
For these purposes, we aimed at (1) portraying the TCR repertoire map of Treg subsets in various tissues of diabetes prone mice (NOD) and healthy mice (C57BL/6J) by NGS sequencing, as well as in the peripheral blood of patients with type 1 diabetes and controls; and (2) generating antigen-specific Tregs.
During the two first years, we have:
- Collected >1500 samples from mouse and human (purified subsets of Tregs as well as CD4 and CD8 Teffs) for TCR mapping
- Launched the TCR sequencing and already obtained >90x106 TCR sequences, representing >2.106 unique TCR clonotypes (out of >2.109 expected TCR sequences we plan to obtain).
- Setup and implemented an NGS data management and processing workflow
- Designed a specific database for TCR sequence repository and analyses
- Performed first-layer analyses of our first sequencing results
- Setup a protocol for insulin-specific Tregs expansion

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