Team:Evry/Project/Mait

   

RiboVax, a new vaccinal vector targeting the MAIT Cells

Mucosal-associated invariant T (MAIT) cells were first described in 1999 and rapidly became a promisive way to carry out immunotherapy, in particular via recent findings revealing their unique anti-bacterial function. This cells represent the most abundant innate-like T-cell population within human beings, comprising up to ~5% of the total T-cell population. They are characterized by the expression of a semi-invariant T-cell Receptor(TCR)(Vα7.2-Jα33/12/20) that recognizes the Major Histocompatibility Complexe (MHC)-like protein 1 (MR1), which presents a bacterial-derived ligand. Furthermore, MAIT cells have been associated with a number of disease settings, including bacterial infections, viral infections, and pro-inflammatory diseases such as multiple sclerosis and psoriasis. Thus, this large T lymphocyte population is likely to have an important role in human health.

General MAIT cells activation process

(1) Internalization of Salmonella by an antigen-presenting cell, either through infection or actively by phagocytosis. (2) Lysis of the bacteria, within endocytic compartments, releases 5-A-RU, which is converted to 5-OE-RU or 5-OP-RU and binds to and stabilizes MR1. (3) The stable MR1 translocates to the cell surface, where it is presented along with other co-stimulatory molecules, e.g., CD80 or CD86. (4) Bacterial components trigger pathogen recognition receptors (PRR), such as TLR8. (5) PRR triggering drives cytokine expression, such as IL-12, and the activation of the inflammosome, resulting in the release of active-IL-18. (6) MAIT cells are activated either by TCR recognition of MR1 in combination with co-stimulatory receptors, e.g., CD28, and/or by cytokines, e.g., IL-12 and IL18. (7) Activated MAIT cells express pro-inflammatory cytokines, e.g., IFNγ, TNFα, and IL-17. (8) These cytokines can directly act anti-bacterially, or recruit and stimulate other immune cells, e.g., neutrophils by IL-17. (9) Activation of MAIT cells upregulates perforin and granzyme B expression. (10) Theoretically, the degranulation of cytotoxic granules into infected cells (target cells), via recognition of MR1, could induce cell death and, thus, the potential clearance of infected cells.

The recognition mechanism of bacterial infections by MAIT cells is based on the bacterial specific riboflavin metabolism (vitamin B2) which is absent in humain beings. This cellular process is dependent of the 5-amino-ribityl-uracil (5-A-RU), an unstable precursor of riboflavin, which attracts the Antigen Presenting Cell (APC) and MAIT cells.

The Curie Institute developped an E.Coli strain (Delta RibE BW25113), in which the genomic RibE enzyme has been deleted. This enzyme is involved in the riboflavin biosynthesis, and more precisely in the chemical transformation of the 5-A-RU in RL-6,7-diMe. Thus, these strain accumulates the 5-A-RU, involved in the MAIT cells attraction, and become a promisive vaccinal vector.

Thus the goal is to express in RiboVax some tumoral antigens specific to each patient, in order to bring them to the CMH-I and CMH-II, and carry out an active and personalized immunotherapy. The following picture explains how in details

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