Oral Presentation CD1-MR1 Workshop 2025

Acetyl-6-formylpterin induces regulatory MAIT cells preventing autoimmunity upon viral infection (#33)

Jeanne Navarre 1 , Lucie Beaudoin 1 , Francois Legoux 2 , Alexandra Corbett 3 , Jacques Beltrand 1 , Agnes Lehuen 1
  1. Institut Cochin, Paris, France
  2. University of Rennes, Rennes, France
  3. Melbourne University, Melbourne, Australia

Type 1 diabetes (T1D) is an autoimmune disease driven by the destruction of insulin-producing pancreatic β cells. MAIT cells are among the immune cell populations that infiltrate the pancreas in non-obese diabetic (NOD) mice, yet their contribution to disease pathogenesis remains unclear (1). Coxsackievirus B4 (CVB4), an enterovirus proposed as an etiologic factor in T1D, provides a relevant model to study virus-induced diabetogenesis (2).

We show that MAIT cells play a pro-diabetogenic role in CVB4-induced T1D. Upon CVB4 infection, Vα19Tg⁺NOD mice developed diabetes more rapidly and frequently, while MR1⁻/⁻NOD mice showed reduced incidence. Treatment with the MR1 antagonist acetyl-6-formylpterin (Ac-6-FP) significantly lowered diabetes incidence and reduced MAIT cell activation (CD69, PD-1) and effector molecule expression (IFN-γ, IL-17, granzyme B), highlighting the TCR-dependent nature of MAIT cell involvement in disease progression.

Moreover, Ac-6-FP induced the acquisition of a regulatory profile of MAIT cells, marked by CD39, CD200R1, CTLA4, and ANXA1 upregulation. This functional shift impacted the immune microenvironment by dampening inflammatory autoreactive CD8⁺ T cell responses and promoting M2-like polarization of infiltrating macrophages. Our results demonstrate that regulatory MAIT cells can be induced, both in vivo and in vitro, supporting their potential as targets for immune modulation.

Using MAIT Nur77-GFP reporter B6CAST mice, we demonstrated that MAIT cells are activated via their TCR during CVB4 infection, providing the first direct evidence of TCR-dependent MAIT cell activation in a viral context. This infection altered the gut microbiota, leading to changes in MR1 ligand availability that promoted pancreatic MAIT cell activation.

These findings uncover a dual role for MAIT cells in virus-induced T1D: pathogenic under pro-inflammatory conditions yet capable of acquiring regulatory properties upon targeted intervention. Our results highlight MAIT cell plasticity and suggest that MR1 ligands like Ac-6-FP could be harnessed to therapeutically modulate MAIT cell function.

  1. Rouxel O, Cagninacci L, Kiaf B, et al. Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes. Nat Immunol. 2017;18(12).
  2. Ghazarian L, Diana J, Beaudoin L, et al. Protection Against Type 1 Diabetes Upon Coxsackievirus B4 Infection and iNKT-Cell Stimulation. Diabetes. 2013;62(11):3785-3796. doi:10.2337/db12-0958