Type 1 Diabetes (T1D) is an auto-immune disease resulting from the destruction by immune cells of insulin-producing β cells in the pancreas. Converging data support the role of Coxsackie virus B4 (CVB4) as an etiologic agent in T1D since it has been observed more frequently in T1D patients. While MAIT cells are activated upon viral infection and can exert an ambivalent role during these infections (influenza, SARS-CoV-2), they are also implicated in T1D pathophysiology in patients and mouse models.
To address the role of MAIT cells, wild-type, MR1-/- or Vα19Tg NOD (Non-Obese Diabetic) mice were infected with CVB4, and we observed that CVB4-induced T1D incidence was increased in Va19Tg mice, and decreased in MAIT cell-deficient mice. During CVB4 infection, MAIT cells were activated in ileum and to a higher level in the pancreas, this organ being more susceptible to CVB4 infection.TCR-dependent activation is critical in several contexts such as bacterial infection and metabolic diseases, however, the involvement of MR1-TCR interaction remains to be addressed in different viral infections. Thus, to assess the potential role of TCR-dependent activation of MAIT cells upon CVB4 infection, mice were treated with acetyl-6-formylpterin (Ac-6-FP). Interestingly, such treatment decreased MAIT cell activation and reduced diabetes incidence. Moreover, Ac-6-FP treatment upon CVB4 infection of both wild-type and Vα19Tg NOD mice switched pancreatic MAIT function toward a regulatory profile. Subsequently, other immune cells (macrophages, T and B cells) infiltrating the pancreas dampened their inflammatory function. These data were obtained by extensive flow cytometry analyses and RNA sequencing of cell-sorted populations.
To further decipher MR1-TCR interaction in CVB4 infection, in vitro studies are presently performed with co-cultures of pancreatic β cells, MAIT cells, and macrophages.Our study will determine the role of MAIT cells and their interaction with MR1 in a complex cellular interplay upon viral infection.