Francisella tularensis induces Th1 like MAIT cells conferring protection against systemic and local infection

Zhe Zhao,Troi Pediongco,Hyun Jae Lee,Xin Yi Lim,Cameron G Williams,Bronwyn S Meehan,James Mccluskey,Tianyuan Zhu,Michael Bramhall,David P Fairlie,Jamie Rossjohn,Maximilien Evrard,Ashraful Haque,Carolin Tumpach,Ming Shi ,Adam Nelson ,Sidonia B G Eckle ,Marcela De Lima Moreira,Alexandra J Corbett,Huimeng Wang,Jeffrey Y W Mak,Zhenjun Chen

doi:10.1038/s41467-021-24570-2

Abstract

Mucosal-associated Invariant T (MAIT) cells are recognized for their antibacterial functions. The protective capacity of MAIT cells has been demonstrated in murine models of local infection, including in the lungs. Here we show that during systemic infection of mice with Francisella tularensis live vaccine strain results in evident MAIT cell expansion in the liver, lungs, kidney and spleen and peripheral blood. The responding MAIT cells manifest a polarised Th1-like MAIT-1 phenotype, including transcription factor and cytokine profile, and confer a critical role in controlling bacterial load. Post resolution of the primary infection, the expanded MAIT cells form stable memory-like MAIT-1 cell populations, suggesting a basis for vaccination. Indeed, a systemic vaccination with synthetic antigen 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil in combination with CpG adjuvant similarly boosts MAIT cells, and results in enhanced protection against both systemic and local infections with different bacteria. Our study highlights the potential utility of targeting MAIT cells to combat a range of bacterial pathogens.

Highlights

Mucosal-associated Invariant T (MAIT) cells are recognized for their antibacterial functions
Its use in humans was discontinued due to the risks associated with administration of a live organism with undetermined genetics, F. tularensis live vaccine strain (LVS) provides a useful model for pathogenicity and immune response research38, and it was previously shown that MAIT cells have a protective role during respiratory infection12,39
To confirm that F. tularensis LVS, a riboflavin biosynthesis proficient bacteria as shown in the database Kyoto Encyclopedia of Genes and Genomes, can stimulate MAIT cells, we used an in vitro activation assay with Jurkat.MAIT.AF7 reporter cells co-cultured with Class I reduced (C1R) Agpresenting cells expressing MR1 (C1R.MR1 cells) as antigen presenting cells, as previously described10

Summary

Introduction

Mucosal-associated Invariant T (MAIT) cells are recognized for their antibacterial functions. Significant MAIT cell accumulation was observed in all organs tested and in the blood at 14 days post infection (dpi), compared to uninfected mice (Fig. 1B–D).

Results

Conclusion