Bacteria license antigen presenting cells for MR1-mediated MAIT cell activation — ASN Events
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Bacteria license antigen presenting cells for MR1-mediated MAIT cell activation (#209)

Tom Williams 1 , Rajesh Lamichhane 1 , Sara de la Harpe 2 , Joel Tyndall 2 , Andrea Vernall 2 , James Ussher 1
  1. Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
  2. School of Pharmacy, University of Otago, Dunedin, New Zealand

MAIT cells are antibacterial T cells that are abundant in liver and mucosal surfaces. The MAIT cell T cell receptor is restricted by MR1, which presents antigens derived from 5-amino-6-d-ribitylaminouracil (5-A-RU), a metabolic precursor of riboflavin synthesis. Many different bacterial species, both pathogenic and commensal, can produce 5-A-RU, and the antigens derived from 5-A-RU can be found in the supernatant of bacterial cultures. Given the abundance and anatomical location of MAIT cells and the multiple sources of 5-A-RU, MR1-mediated MAIT cell activation must be tightly regulated to prevent immunopathology.

 Previous work has suggested that TLR agonists and NFkB may regulate MR1 surface expression and E. coli-induced MAIT cell activation1. In this study, we have dissected the regulation of MR1-mediated MAIT cell activation by bacteria. Using THP1.hMR1 cells, we found that non-ligand producing bacteria (E. coli ΔribD and Enterococcus faecalis) and TLR-1 and -6 agonists were able to increase MR1 surface expression in the absence of 5-A-RU. When combined with 5-A-RU, non-ligand-producing bacteria strongly enhanced MR1 surface expression compared with 5-A-RU alone; in contrast, no enhancement was seen with TLR agonists or with lysed bacteria. Inhibiting phagocytosis with cytochalasin D significantly reduced E. coli ΔribD + 5-A-RU-mediated MR1 upregulation. Inhibiting ER-Golgi transport with brefeldin A completely inhibited MR1 upregulation to all stimuli. Finally, we confirmed that MAIT cell activation in response to 5-A-RU was enhanced by non-ligand producing bacteria.

 We propose a model whereby MAIT cell activation is enhanced in the presence of bacteria, both through antigen-presenting cell (APC) licensing via pattern recognition receptors and through delivery of 5-A-RU to the phagosome. From the phagosome, 5-A-RU (or the pyrimidine ligand that is derived from it) accesses the ER by an unknown mechanism before trafficking to the cell surface. Therefore, robust MR1-mediated MAIT cell activation requires phagocytosis of tissue-invasive bacteria by APCs.

  1. 1. Ussher JE, van Wilgenburg B, Hannaway RF, Ruustal K, Phalora P, Kurioka A, Hansen TH, Willberg CB, Phillips RE, Klenerman P (2016) TLR signaling in human antigen-presenting cells regulates MR1-dependent activation of MAIT cells. Eur J Immunol 46: 1600-1614.