MAIT · Evolutionary conserved T cells specific for a microbial metabolite: deciphering their development in the thymus and mapping their interactions with the gut microbiota in vivo.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-04-01 → 2018-03-31
- EU contribution
- €185,076
- Participants
- 1
- Scheme
- MSCA-IF-EF-RI
Lines connect the coordinator with its partners.
Results in brief
Evolutionary conserved T cells specific for a microbial metabolite: deciphering their development in the thymus and mapping their interactions with the gut microbiota in vivo.
Context The human intestine is colonized by 1012 to 1014 non-pathogenic microbes. These microbes (viruses, bacteria, parasites and fungi) constitute the intestinal microbiota. There is an increasing recognition of the role of the microbiota in human health. In particular, the occurrence of inflammatory diseases (Crohn’s disease, ulcerative colitis), metabolic diseases (obesity, diabetes) and cancer has been linked to dysbiosis of the intestinal microbiota. Therefore, there is a need for a better understanding of the mechanisms of action of the microbiota on the host. Overall objectives of the project The overall goal of the project is to determine the effect of the microbiota on the host immune system. In particular, our research is focusing on the effect of microbial metabolites on T lymphocytes. Metabolites derived from the vitamin B2 synthesis pathway, a pathway present in most bacteria and yeasts but absent in mammals, are recognized by a population of T lymphocytes. The specific aims of this project are: 1. To determine how T lymphocytes specific for microbial metabolites develop in the thymus. 2. To define the role of the microbiota in the function of T lymphocytes specific for microbial metabolites. Conclusions of the action 1. We have identified the molecular pathway controlling key events of the thymic development of T lymphocytes specific for microbial metabolites. 2. We have determined how metabolite-specific T cells react and expand in response to the microbiota.
Data: CORDIS, © European Union
Project objective
Mucosal Associated Invariant T cells (MAITs) represent an evolutionary conserved subset that express a semi-invariant TCR recognizing a new class of microbial metabolite antigens presented by the MHC class Ib molecule, MR1. In addition to their wide anti-microbial specificity, the high inter-species conservation of both MR1 and invariant TCR infers an important biological role for MAITs. MAITs are abundant in human blood (1-8 % of T cells), mucosa and liver (20-50%). After development in the thymus, MAITs reach the periphery where they acquire a memory phenotype and expand in a process that requires a commensal flora, indicating that MAITs play a role in host-commensals interactions. Admittedly MAITs blood frequency is modified in several pathologies in which dysbiosis of the gut microbiota has been implicated such as IBD, MS, type 2 diabetes and obesity.MAITs were first described over 15 years ago by the Host lab, but the understanding of their development has remained limited because of their scarcity in laboratory mice. Here we will overcome this challenge by using a new mouse strain with increased frequency of polyclonal MAITs.Using my expertise acquired in the US and building on unique tools, we will:1) Define MAITs lineage: we will use a transcriptomic approach together with dedicated transgenic mouse models to determine how MAITs selection leads to their specific differentiation program in the thymus.2) Elucidate the mechanisms of MAITs peripheral expansion: we will use germ-free mice and modified bacteria to map the in vivo availability of MAITs ligands upon colonization with commensal microbes.The proposal will provide insights into an evolutionary conserved model of interactions between the adaptive immune system and the gut microbiota.By enabling me to permanently re-integrate the EU, this project will also guarantee transfer of technologies and creation of new bounds between the US and the EU, and will increase the EU competitiveness.
Original text from CORDIS.
Participants
- INSTITUT CURIE · ParisCoordinatorFrance
Links
- View on CORDIS
- DOI: 10.3030/706353
- https://science.institut-curie.org/research/integrated-biology/u932-immunity-and-cancer/team-lantz/
Data: CORDIS, © European Union