An overview on the identification of MAIT cell antigens

Abstract

Mucosal associated invariant T (MAIT) cells are restricted by the monomorphic MHC class I-like molecule, MHC-related protein-1 (MR1). Until 2012, the origin of the MAIT cell antigens (Ags) was unknown, although it was established that MAIT cells could be activated by a broad range of bacteria and yeasts, possibly suggesting a conserved Ag. Using a combination of protein chemistry, mass spectrometry, cellular biology, structural biology and small molecule chemistry, we discovered MR1 ligands derived from folic acid (vitamin B9) and from an intermediate in the microbial biosynthesis of riboflavin (vitamin B2). While the folate derivative 6-formylpterin generally inhibited MAIT cell activation, two riboflavin pathway derivatives, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil and 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil, were potent MAIT cell agonists. Other intermediates and derivatives of riboflavin synthesis displayed weak or no MAIT cell activation. Collectively, these studies revealed that in addition to peptide and lipid-based Ags, small molecule natural product metabolites are also ligands that can activate T cells expressing αβ T-cell receptors, and here we recount this discovery.

Development of mucosal‐associated invariant T cells

“…13,18,19 Conversely, because MAIT cell numbers in laboratory mice are very low, and monoclonal antibodies against the invariant mouse MAIT TCRa chain do not exist, Va19Ja33 transgenic mice were established to investigate the biology of mouse MAIT cells. 16,20 The discovery of riboflavin derivatives as antigens (Ags) for MAIT cells 21,22 (described in this issue by Kjer-Nielsen, Corbett and colleagues 23 ), coupled with the production of MR1 tetramers that incorporate these Ags, 5 has fueled new studies into the development and function of MAIT cells. These tetramer reagents now provide a basis for distinguishing MAIT cells from other T-cell populations that share similar phenotypic markers.…”

Characterization of Human Mucosal‐associated Invariant T (MAIT) Cells

“…MAIT cells play a key role in protective immunity to infection by riboflavinproducing microbes, as demonstrated for Mycobacterium bovis BCG, Klebsiella pneumoniae, Escherichia coli, Francisella tularensis, and Legionella longbeachae (e.g., Chua et al, 2012;Cui et al, 2015;Georgel, Radosavljevic, Macquin, & Bahram, 2011;Meierovics, Yankelevich, & Cowley, 2013;Wang et al, 2018;reviewed in Godfrey et al, 2019;Kjer-Nielsen et al, 2018). MAIT cell immune function includes the production of proinflammatory cytokines TNF, IFNγ, IL-17A (Dusseaux et al, 2011;Le Bourhis et al, 2013) and in cytotoxicity (Kurioka et al, 2015;Le Bourhis et al, 2013).…”

“…Mucosal‐associated invariant T (MAIT) cells are a subset of unconventional T cells that express an αβ T cell receptor (TCR) and are restricted by the monomorphic major histocompatibility complex (MHC) class I–like molecule MHC‐related protein 1 (MR1) (Hashimoto, Hirai, & Kurosawa, ; Porcelli, Yockey, Brenner, & Balk, ; Tilloy et al., ; Treiner et al., ). Unlike conventional T cells (which recognize peptide antigens [Ags]) or natural killer T (NKT) cells (which recognize glycolipid Ags; Rossjohn, Pellicci, Patel, Gapin, & Godfrey, ), MAIT cells recognize metabolite Ags (Corbett et al., ; Kjer‐Nielsen et al., ; reviewed in Eckle et al., ; Kjer‐Nielsen et al., ). The most potent MAIT cell Ags, which activate all MAIT cells, originate from an intermediate in the microbial biosynthesis of riboflavin (vitamin B 2 ), 5‐amino‐6‐ D ‐ribitylaminouracil (5‐A‐RU).…”

“…Riboflavin biosynthesis is absent in mammals, including humans, but is present in most bacteria and yeast, providing a microbial signature for MAIT cell surveillance. Indeed, MAIT cells are stimulated by and play a key role in protection from riboflavin-producing microbes (reviewed in Kjer-Nielsen et al, 2018). Furthermore, MAIT cells can also respond to viruses in an MR1-Ag independent manner (reviewed in Ussher, Willberg, & Klenerman, 2018), and their role in autoimmune-and immune-mediated diseases and cancer is being investigated (reviewed in Godfrey, Koay, McCluskey, & Gherardin, 2019;Rouxel & Lehuen, 2018), including their potential role in drug allergies (Keller et al, 2017).…”

MAIT cells: the end of the beginning?

“…The Special Feature reviews in this issue start with the historical perspective on MAIT cells – in terms of both their discovery and their evolution – which may give some clue as to their critical and overlapping functions . This leads naturally on from the cells themselves to what they recognize – a major set of discoveries which has led to an explosion of interest in the field . The development of this cell type and its selection in the thymus is next explored, an area that can give insight into not only MAIT cell biology but that of other related cell types .…”