Ontogeny of MAIT Cells in Neonates and Hematopoietic Stem Cell Transplant Recipients

Study Overview
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Brief Summary
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The objective of this study is 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 with MAIT cell maturation and function in neonates and HSCT recipients; and 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

Detailed Description
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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 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. 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. 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, 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.

Official Title
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Ontogeny of MAIT Cells in Neonates and Hematopoietic Stem Cell Transplant Recipients

Conditions
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Term and Preterm Neonates (24-41 Weeks Gestational Age), Hematopoietic Stem Cell Transplant Recipient Children

Intervention / Treatment
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* Other: Tubes fund recovery blood count
* Other: the rest of the blood test and stool sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: neonates 24-41 weeks gestational age hematopoietic stem cell transplant recipient children (< 18 years old, donor source: cord blood or genoidentical donor) Exclusion Criteria: neonates : chromosomal abnormalities detected before birth source of HSCT: phenol-identical donors

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| neonates<br>neonates 24-41 weeks gestational age | Other: Tubes fund recovery blood count<br>* Tubes fund recovery of blood counts among newborns<br>|
| children<br>hematopoietic stem cell transplant recipient children (< 18 years old, donor source: cord blood or genoidentical donor) | Other: the rest of the blood test and stool sample<br>* blood samples on the recovery kinetics after transplant. The rest of the blood test and stool sample done as part of a routine examination.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MAIT cell numbering neonates after birth | Absolute number, percentage and phenotype of MAIT cells by flow cytometry in the circulating blood after birth according to gestational age and / or maternal-fetal infections (IMF), or after allogeneic HSCT according to the origin of HSCs. | to 60days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute number of MAIT | Absolute number and percentage of MAIT among mothers of infants on the day of delivery and in geno-identical donors before transplantation. | to 60days | 
| Absolute number of other immune cell populations | Absolute number and percentage of other immune cell populations by flow cytometry on the same blood samples. | to 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MAIT (Mucosal-Associated Invariant T) cells, Gut microbiota, Preterm birth, Hematopoietic stem cell transplantation, Microbial infections