Cysteinylation of MHC class II ligands: Peptide endocytosis and reduction within APC influences T cell recognition

Peptides; bind cell surface MHC class II proteins to yield complexes capabl e of activating CD4(+) T cells. By contrast, protein Ags require internaliz ation and processing by APC before functional presentation. Here, T cell re cognition of a short peptide in the context of class II proteins occurred o nly after delivery of this ligand to mature endosomal/lysosomal compartment s within APC. Functional and biochemical studies revealed that a central cy steine within the peptide was cysteinylated, perturbing T cell recognition of this epitope. Internalization and processing of the modified epitope by APC, was required to restore T cell recognition. Peptide cysteinylation and reduction could occur rapidly and reversibly before MHC binding. Cysteinyl ation did not disrupt peptide binding to class II molecules, rather the mod ified peptide displayed an enhanced affinity for MHC at neutral pH. However , once the peptide was bound to class II proteins, oxidation or reduction o f cysteine residues was severely limited. Cysteinylation has been shown to radically influence T cell responses to MHC class I ligands. The ability of professional APC to reductively cleave this peptide modification presumabl y evolved to circumvent a similar problem in MHC class II ligand recognitio n.