DS0404 - Innovation biomédicale

Ontogeny of MAIT cells in neonates and hematopoietic stem cell transplant recipients – NEOMAIT

Submission summary

The mucosa-associated invariant T (MAIT) cells are innate-like T cells with restricted T cell receptor (TCR) usage, which are preferentially localized in mucosal tissues and respond to microbial infection by rapidly producing cytokines and cytotoxic effectors. They recognize the non-classical MHC-related molecule MR1. MAIT cells react against a newly identified class of antigens presented by MR1: Riboflavin (Rib) precursors, which are found in most bacteria and yeasts. MAIT cells are decreased in the blood of patients with bacterial infections and are protective in experimental models of infection. Currently, very little is known about the ontogeny of MAIT cells in the human, because of the difficulty to follow longitudinally their development. Cross-sectional studies have identified only the initial (cord blood) and final (adult subjects) steps of human MAIT cell maturation program. Moreover, there are no data on relationships between human MAIT cell expansion and maturation, and gut microbiota development. Given the potential importance of MAIT cells in protection from microbial infections at epithelial surfaces, we will investigate the maturation dynamics of MAIT cells in relation with gut microbiota diversity and function in two clinical settings characterized by a high predisposition to severe microbial infections before the establishment of protective adaptive immunity, namely i/ the neonatal period and ii/ the early immune reconstitution period following allogeneic hematopoietic stem cell transplantation (HSCT) in children. Our study will combine multiparametric phenotypic and functional characterization of MAIT cells with the use of new molecular microbiota analytic methodology (high throughput sequencing, metagenomics, Rib microbiology) to determine how the presence or functionality of MAIT cells is influenced by the gut microbiota, and vice versa.
We will address four aims: 1/ To determine the rate and kinetics of MAIT cell expansion and maturation in neonates in relation with gestational age, and in HSCT recipient children in relation with the source of donor stem cells, 2/ To correlate gut microbiota diversity and function (availability of Rib metabolites) with MAIT cell maturation and function in neonates and HSCT recipients, 3/ To link MAIT cells and gut microbiota composition with microbial infections and severe intestinal inflammatory events in term and preterm neonates, and in HSCT recipients, 4/ To integrate all these data in order to define a model of interactions between MAIT cells, gut microbiota composition, antimicrobial defense and gut mucosal protection.
Our consortium is composed of three independent research teams, experts in innate immunity, microbial ecology and MAIT cell biology, three independent clinical teams providing exceptional resources to patient samples, and one team providing expertise for methodology and statistical analysis. Their synergistic interaction will offer the various complementary expertise that is necessary for this project.
This project will decipher how MAIT cell numbers or functions are influenced by the gut microbiota composition (in particular the availability of MR1 ligands), and reciprocally, how MAIT cells regulate or control expansion of gut microbiota components competing with opportunistic or pathogenic bacteria or responsible for infections. Ultimately, this study will determine how and when gut microbiota and MAIT cell interactions are involved in the control of severe infectious or intestinal inflammatory events in high risk infants, an indispensable step to design predictive biomarkers and ultimately propose new therapeutic options.

Project coordination

Sophie Caillat (Institut National de la Santé et de la Recherche Médicale (UMR1149))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

APHP Assistance Publique-Hôpitaux de Paris
Micalis Microbiologie de l'Alimentation au service de la Santé
IC Institut Curie - Section de recherche
APHP Assistance Publique-Hôpitaux de Paris
INSERM Institut National de la Santé et de la Recherche Médicale (UMR1149)
APHP Assistance Publique-Hôpitaux de Paris
APHP Assistance Publique-Hôpitaux de Paris

Help of the ANR 561,533 euros
Beginning and duration of the scientific project: January 2015 - 36 Months

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