On page 1201, Huang et al. find that an antigen-presenting protein suffers from an identity crisis: it looks like MHC class I but behaves like MHC class II.
This molecule, MR1, is recognized by a subset of gut-roving T cells. When MR1 carries the right antigen, these T cells suppress gut inflammation, but the identity of that antigen is a mystery. Because MR1 is structurally similar to MHC class I molecules, which usually pick up proteasome-processed peptides in the ER, MR1 was thought to do the same.
This notion is now disproved by Huang et al., who show that MR1-expressing cells treated with proteasome inhibitors or lacking ER peptide–loading chaperones can still activate these T cells. Instead, they found, MR1 picked up its antigens in endosomes, where MHC class II molecules get theirs.
MR1 bound to a chaperone called the invariant chain, which ferries MHC class II molecules from the ER into endosomes. There, it bound another chaperone, called DM, which loads them up with peptides. MR1-expressing cells that lacked the invariant chain were unable to activate gut T cells, whereas high levels of this protein increased their activation.
The immune-suppressing ability of MR1-activated T cells suggests that they might prevent the gut from attacking its helpful resident flora. The authors therefore speculate that the MR1 ligand might be derived from one or more of these residents.