Covering All the Bases: Complementary MR1 Antigen Presentation Pathways Sample Diverse Antigens and Intracellular Compartments

Abstract

The ubiquitously expressed, monomorphic MHC class Ib molecule MHC class I-related protein 1 (MR1) presents microbial metabolites to mucosal-associated invariant T (MAIT) cells. However, recent work demonstrates that both the ligands bound by MR1 and the T cells restricted by it are more diverse than originally thought. It is becoming increasingly clear that MR1 is capable of presenting a remarkable variety of both microbial and non-microbial small molecule antigens to a diverse group of MR1-restricted T cells (MR1Ts) and that the antigen presentation pathway differs between exogenously delivered antigen and intracellular microbial infection. These distinct antigen presentation pathways suggest that MR1 shares features of both MHC class I and MHC class II antigen presentation, enabling it to sample diverse intracellular compartments and capture antigen of both intracellular and extracellular origin. Here, we review recent developments and new insights into the cellular mechanisms of MR1-dependent antigen presentation with a focus on microbial MR1T cell antigens.

The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation

“…However, to effectively leverage the potential of these cells in prophylactic and therapeutic applications, a better understanding of the MR1-MAIT cell axis is needed. In particular, the cellular and molecular mechanisms governing MR1 loading and trafficking are an area of ongoing research ( 10 , 31 , 36 , 39 , 41 ).…”

“…The monomorphic major histocompatibility complex (MHC) class I-related protein 1 (MR1) presents small-molecule metabolites to mucosal-associated invariant T (MAIT) cells ( 1 , 2 , 3 ). While the full spectrum of MR1 ligands is still being elucidated ( 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ), the best characterized MAIT-activating MR1 ligands are derivatives of pyrimidine intermediates of riboflavin biosynthesis, a pathway specific to certain fungi and bacteria and, thus, intrinsically non-self for humans ( 1 , 11 ). Accordingly, MAIT cells are activated upon recognition of MR1 ligands derived from a variety of microbes capable of riboflavin synthesis such as Escherichia coli ( E.coli ), Salmonella typhimurium , and Mycobacterium tuberculosis ( 12 , 13 , 14 , 15 ).…”

Understanding and modulating the MR1 metabolite antigen presentation pathway

“…Classically, the presentation of these endogenous and exogenous sources of protein-derived antigen by MHC molecules is handled separately by MHC class I and II molecules, which have differing trafficking pathways and co-factors (Rock et al, 2016). Intriguingly, cellular evidence indicates that MR1 alone can achieve this feat, although the mechanisms that are still being delineated, particularly regarding the route for presentation of antigen from intracellular sources such as from intracellular bacteria, which still remains unclear (Kulicke et al, 2020;McWilliam and Villadangos, 2018). However, the pathway for loading antigens from the extracellular milieu is much more well defined from several recent studies (Karamooz et al, 2019;McWilliam et al, 2016;McWilliam et al, 2020;Salio et al, 2020).…”

The P5-ATPase ATP13A1 modulates MR1-mediated antigen presentation

“…However, to effectively leverage the potential of these cells in prophylactic and therapeutic applications, a better understanding of the MR1-MAIT cell axis is needed. In particular, the cellular and molecular mechanisms governing MR1 loading and trafficking are incompletely defined (10, 31, 39, 41).…”

“…The monomorphic major histocompatibility complex (MHC) class I-related protein 1 (MR1) presents small molecule metabolites to mucosal-associated invariant T (MAIT) cells (1–3). While the full spectrum of MR1 ligands is still being elucidated (2, 4–10), the best characterized MAIT-activating MR1 ligands are derivatives of pyrimidine intermediates of riboflavin biosynthesis, a pathway specific to certain fungi and bacteria and, thus, intrinsically non-self for humans (1, 11). Accordingly, MAIT cells are activated upon recognition of MR1 ligands derived from a variety of microbes capable of riboflavin synthesis such as Escherichia coli ( E.coli ), Salmonella typhimurium , and Mycobacterium tuberculosis (12–15).…”