MAIT cells contribute to protection against lethal influenza infection in vivo

Bonnie Van Wilgenburg,Criselle D’Souza,Simone Nüssing,Ming Shi ,Axel Kallies,Sneha Sant,Sidonia B G Eckle ,Alexandra J Corbett,Katherine Kedzierska,Huimeng Wang,Xiaoyun Jia ,James Mccluskey,Zhe Zhao,Zhenjun Chen,Liyen Loh,Marios Koutsakos,Zhongfang Wang,Patrick C Reading,Catarina Almeida ,Paul Klenerman,Lyudmila Kostenko,Dale I Godfrey,Troi Pediongco ,Bronwyn S Meehan,Tsc Hinks

doi:10.1038/s41467-018-07207-9

Abstract

Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo. Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulate and are activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post-infection. Activation is modulated via cytokines independently of MR1. MAIT cell-deficient MR1−/− mice show enhanced weight loss and mortality to severe (H1N1) influenza. This is ameliorated by prior adoptive transfer of pulmonary MAIT cells in both immunocompetent and immunodeficient RAG2−/−γC−/− mice. Thus, MAIT cells contribute to protection during respiratory viral infections, and constitute a potential target for therapeutic manipulation.

Highlights

Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection
CD25 expression on conventional CD4+ T cells peaked at 7 dpi, whilst CD69 continued to increase over the course of the experiment and the highest levels were detected on CD4+ and CD8+ T cells at 13 dpi
These findings are consistent with our previous human in vitro observations in which we demonstrated MHC related protein-1 (MR1)-independent MAIT cell activation in response to exogenous cytokines[20,21] or to IAV21

Summary

Introduction

Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells express a semi-invariant αβ T cell receptor (TCR)[7] shown to recognise metabolic derivatives of highly-conserved riboflavin biosynthetic pathways[8,9], that are expressed by a wide range of bacteria, mycobacteria and yeasts[10] These molecules are usually shortlived, but are stabilised by MR1, and include 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), which is a potent MAIT cell ligand[11], and can be loaded onto MR1 to form specific tetramers to track human and murine MAIT cells[9,12]. These data indicate that MAIT cells are activated and contribute to protection against a lethal viral challenge in vivo

Methods

Results

Conclusion