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.
Highlights
The immune system is traditionally thought of as dichotomous
While classical mucosal-associated invariant T (MAIT) cells are defined by expression of the TRAV1-2 TCRα chain, more recent work has identified TRAV1-2− T cells that are activated in an MHC I-related protein 1 (MR1)-dependent manner, expanding the family of MR1-restricted T cells (MR1Ts) [5, 7,8,9,10,11]
We identified a TRAV12-2+ MR1T clone that responds to an unidentified ligand from Streptococcus pyogenes (S. pyogenes), a bacterium that does not express the enzymes of the riboflavin biosynthetic pathway [10]
Summary
The immune system is traditionally thought of as dichotomous. On the one hand, the innate immune system is activated by broadly conserved pathogen-associated molecular patterns (PAMPs) detected by germline-encoded pattern recognition receptors. Since all remain to be identified, it is still unknown whether any of these potential self-ligands are present in healthy cells and may play a role as chaperone-like molecules such as Ii, serve as MR1T antigens that contribute to inflammation, or constitute regulatory MR1 ligands involved in immune modulation and tolerance.
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