Oral Presentation CD1-MR1 Workshop 2025

Microbiota of type 1 diabetic children induces MAIT cell dysfunction and alters intestinal mucosa (#31)

Adrien Caffiers 1 , Léo Bertrand 1 , Carole Passone 1 2 , Lucie Beaudoin 1 , Gaëlle Vermillac 1 2 , Benoit Chassaing 1 3 , Jacques Beltrand 1 2 , Agnès Lehuen 1
  1. Immunology and genetics of diabetes and endocrine diseases, Institut Cochin, Paris, France
  2. Pediatric endocrinology and diabetology, Hôpital Universitaire Necker Enfants Malades, Paris, France
  3. Microbiome-Host Interaction, Institut Pasteur, Paris, France

Type 1 Diabetes (T1D) is an auto-immune disease characterized by the destruction of β-pancreatic cells within Langerhans islets. Both innate and adaptative immune systems are involved in the pathogenesis of the disease. MAIT cells are innate-like T cells that recognize molecules produced in a microbiota dependent manner. Our team showed that MAIT cells are capable of being directly cytotoxic against beta cells1. However, gut MAIT cells are protective against T1D development in a Th17-dependent manner, affecting both intestinal microbiota and gut immunity1,2. Here, we further investigated the impact of gut microbiota in the development of T1D.

 

We collected blood and feces from a cohort of children, either healthy or with recent-onset T1D. MAIT cells were analyzed by flow cytometry, bulk and scRNA sequencing. Feces were analyzed in vitro for their ability to activate MAIT cells and were transferred into 4-week-old gnotobiotic non-obese diabetic (NOD) mice depleted of their original microbiota.Intestinal immune and epithelial cells from these gnotobiotic mice were analyzed by flow cytometry, bulk and scRNA sequencing.

 

Blood MAIT cells are overactivated and cytotoxic in patients, especially in younger children. Mouse MAIT cells co-cultured with feces extracts from patients displayed an impaired maturation state that scales with patient blood MAIT cell alterations. Transfer of feces from patients in NOD mice induces lower activation of immune cells in the gut, as well as increased pancreatic islet infiltration and diabetes incidence. RNA sequencing analyses reveal a weakening of MAIT cell Th17 transcriptomic program, and further alterations of immune and epithelial cells in gnotobiotic NOD mice transferred with T1D microbiota.

 

Our results reveal that microbiota from diabetic patients lowers intestinal immune functionality in gnotobiotic mice, impairing gut integrity and thereby promoting autoimmunity. Blood analyses in patients suggest that a similar pathogenic mechanism is also at play in patients.

  1. Rouxel, O. et al. Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes. Nat. Immunol. 18, 1321–1331 (2017).
  2. Rouland, M. et al. Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia. Gut 71, 296–308 (2022).