Oral Presentation CD1-MR1 2024

MR1-dependent activation of MAIT cells by liver-stage malaria parasites (#31)

Phoebe M Dewar 1 , Christopher D Goodman 2 , Anton Cozijnsen 2 , Troi J Pediongco 1 , Adam G Nelson 1 , Eleanor M Eddy 1 , Sheliajen Alacantra 1 , Charlie Jennison 2 , Lisa H Verzier 3 , Justin A Boddey 3 , Huimeng Wang 1 , Ashraful Haque 1 , Geoffrey I McFadden 2 , William R Heath 1 , Moriya Tsuji 4 , James McCluskey 1 , Daniel Fernandez-Ruiz 1 , Jordana G Coelho-dos-Reis 5 6 , Marcela de Lima Moreira 1 , Sidonia B.G Eckle 1
  1. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  2. School of BioSciences, University of Melbourne, Melbourne, VIC, Australia
  3. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  4. Aaron Diamond AIDS Research Center, Department of Medicine, , Columbia University Irving Medical Center, New York, United States
  5. Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
  6. Department of Microbiology, Institute for Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Mucosal-associated invariant T (MAIT) cells are a subset of pro-inflammatory innate-like T cells that are highly abundant in human tissues and recognize small molecule metabolite antigens presented by the MHC class-I-like molecule, MR1. MAIT cells are found in almost all mammals, whereby the MAIT-MR1 axis is highly conserved, suggesting an important physiological function linked to metabolite antigen sensing. A well-characterised function of MAIT cells is protection during bacterial and fungal infections upon recognition of the MR1-presented antigen 5-OP-RU, a riboflavin-synthesis-derived metabolite. Whether MAIT cells contribute to immunity from riboflavin-deficient parasites upon recognition of a novel antigen is unclear. Because of the large frequency of MAIT cells in the human liver and the well-established protective capacity of CD8+ T cells during liver-stage malaria, we sought to characterise the role of MAIT cells during liver-stage malaria using a mouse model of liver-stage infection. Current results indicate that two days following infection with Plasmodium berghei, the liver parasite burden of MR1-/- C57BL/6 mice is significantly higher than that of MAIT cell-proficient wild-type mice. This suggests that MAIT cells may contribute to protection. In vitro, when PMA-differentiated THP-1 cells were co-incubated with Plasmodium falciparum or P. berghei sporozoites and MAIT cells enriched from healthy human blood, MAIT cells displayed a polyfunctional pro-inflammatory cytokine and cytotoxic response. Assays with MR1 blockade or MR1 overexpressing and knock-out THP-1 cells, demonstrated activation was dependent on antigen presentation by MR1. As Plasmodium spp. lack the riboflavin biosynthesis pathway, this data alludes to the existence of a novel Plasmodium liver-stage-infection-derived MAIT cell antigen. Consequently, our findings suggest MAIT cells play a protective role in the immune response to liver-stage malaria and have the potential to provide the conceptual basis for a broad-spectrum MAIT cell-based malaria vaccine for Plasmodium infection.