Cells invoke a ‘plan B’ to alert immune cells when defects or viral infection causes the cells’ normal antigen processing pathways to go awry, according to a study published in Nature Immunology. These findings may have bearing in several autoimmune diseases, such as psoriasis, that are associated with this molecular system.
Peptides derived from aberrant tumor proteins, viruses, or other intracellular pathogens can be displayed by highly polymorphic molecules called MHCI - key components of the immune system. When specific immune cells recognize these complexes, it triggers them to kill the targeted cell. Hence many pathogens attempt to evade immune surveillance by inhibiting the protein processing pathway leading to peptide loading onto the MHC molecules.
Nilabh Shastri and colleagues find cells that monitor the functionality of ERAAP-an enzyme found in the endoplasmic reticulum that trims peptides loaded onto MHC binding pockets. Loss of ERAAP triggers cells to present a unique peptide, FL9, in conjunction with a non-classical MHC molecule, Qa-1. Specific T cells capable of recognizing this Qa-1-FL9 complex trigger an immune response by producing molecules that kill these Qa-1-FL9+ cells. The authors found that these Qa-1-FL9-responsive T cells are relatively abundant in mice where they can eliminate cells that become defective for ERAAP-mediated peptide processing.