Oral Presentation CD1-MR1 2024

MAIT cells regulate lung inflammation during severe viral pneumonia. (#32)

Youenn Jouan 1 , Loïc Gonzalez 1 , Aurélie Darbois 2 , Anastasia du Halgouêt 2 , Emilie Barsac 1 , Roxane Lemoine 1 , Guy Ilango 1 , Martin Mestdagh 2 , Marie Brevet 3 , Mustapha Si-Tahar 1 , Thomas Baranek 1 , Olivier Lantz 2 , Christophe Paget 1 , Marion Salou 2
  1. CEPR, INSERM U1100, Tours, France
  2. INSERM U932, Institut Curie, Paris, France
  3. Cypath-rb, Lyon, France

Viral pneumonia can culminate in acute respiratory distress syndrome (ARDS), a severe form of respiratory failure with high mortality. Uncontrolled local inflammatory response and impaired tissue repair processes are hallmarks of viral ARDS. Using experimental models and/or clinical studies, we and others reported evidence for a role of MAIT cells in severe viral pneumonia/ARDS (1-5). However, the role and functions of MAIT cells in viral pneumonia/ARDS immunopathology remain unknown. To explore this, we combined two complementary experimental models of severe Influenza A virus (IAV) infections (H1N1 and H3N2 strains) mimicking various clinical pictures of ARDS.

In both IAV models, MAIT cell-deficient mice displayed increased lethality. This was not associated with uncontrolled viral replication, pointing towards a role in the regulation of the inflammatory response and/or tissue repair. Flow cytometry and transcriptomic data indicated that lung MAIT cells rapidly displayed an activated phenotype. The use of Cd4cre x Ifnar1fl/fl mice indicated that MAIT activation was dependent on type I IFN signaling. Interestingly, lung MAIT cells displayed important transcriptional and functional reprogramming throughout the infection. While cytotoxic and pro-inflammatory profile (IFN-γ, IL-17A, GzB) characterized MAIT cells in the early phases of infection, anti-inflammatory and pro-repair signature (Areg, IL-22) dominated later on. MAIT cell deficiency led to increased tissue damages associated with higher levels of inflammatory cytokines and recruitment of inflammatory monocytes and MoDC. Finally, we show that 5-OP-RU treatment following infection confers MAIT cell-dependent protection.

Thus, lung MAIT cells exert protective functions during the course of severe viral pneumonia, which can be enhanced through cognate stimulation. Altogether, MAIT cells emerge as key natural actors and potential targets in local immune regulation during viral respiratory infections.

  1. Jouan, Y. et al. Phenotypical and functional alteration of unconventional T cells in severe COVID-19 patients. J Exp Med 217, e20200872 (2020).
  2. Flament, H. et al. Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity. Nat Immunol 22, 322–335 (2021)
  3. Parrot, T. et al. MAIT cell activation and dynamics associated with COVID-19 disease severity. Sci Immunol 5, eabe1670 (2020).
  4. Loh, L. et al. Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation. Proc. Natl. Acad. Sci. U.S.A. 113, 10133–10138 (2016).
  5. van Wilgenburg, B. et al. MAIT cells are activated during human viral infections. Nat Commun 7, 11653 (2016).