How MHC class II molecules acquire peptide cargo: Biosynthesis and trafficking through the endocytic pathway

The antigen-specific receptors of T lymphocytes rely on products of the major histocompatibility complex (MHC) to recognize and engage antigen. MHC molecules display antigen on the cell surface in the form of small peptides, generated intracellularly by fragmentation of the intact protein antigen. They acquire these peptides at distinct intracellular locations: In the endoplasmic reticulum (ER), class I molecules bind peptides derived from cytosolic proteins, whereas class II molecules acquire their peptide cargo in an endocytic compartment. Sequestration of class II molecules from the constitutive secretory pathway is mediated by their interaction with an additional polypeptide, the invariant chain (Ii). The Ii contains sorting signals in its cytoplasmic tail that target class II molecules to the endocytic pathway where they encounter peptides generated from protein antigens that have also accessed this route.