A NONPOLYMORPHIC MAJOR HISTOCOMPATIBILITY COMPLEX CLASS IB MOLECULE BINDS A LARGE ARRAY OF DIVERSE SELF-PEPTIDES

Unlike the highly polymorphic major histocompatibility complex (MHC) c lass Ia molecules, which present a wide variety of peptides to T cells , it is generally assumed that the nonpolymorphic MHC class Ib molecul es may have evolved to function as highly specialized receptors for th e presentation of structurally unique peptides. However, a thorough bi ochemical analysis of one class Ib molecule, the soluble isoform of Qa -2 antigen (H-2SQ7(b)), has revealed that it binds a diverse array of structurally similar peptides derived from intracellular proteins in m uch the same manner as the classical antigen-presenting molecules. Spe cifically, we find that SQ7(b) molecules are heterodimers of heavy and light chains complexed with nonameric peptides in a 1:1:1 ratio. Thes e peptides contain a conserved hydrophobic residue at the COOH terminu s and a combination of one or more conserved residue(s) at P7 (histidi ne), P2 (glutamine/leucine), and/or P3 (leucine/asparagine) as anchors for binding SQ7(b). 2 of 18 sequenced peptides matched cytosolic prot eins (cofilin and L19 ribosomal protein), suggesting an intracellular source of the SQ7(b) ligands. Minimal estimates of the peptide reperto ire revealed that at least 200 different naturally processed self-pept ides can bind SQ7(b) molecules. Since Qa-2 molecules associate with a diverse array of peptides, we suggest that they function as effective presenting molecules of endogenously synthesized proteins like the cla ss Ia molecules.