LARGE PROTEIN-FRAGMENTS AS SUBSTRATES FOR ENDOCYTIC ANTIGEN CAPTURE BY MHC CLASS-II MOLECULES

Although the binding sites of MRC class II molecules can accommodate l onger ligands, peptides of 15 to 20 residues are the primary form of p rocessed Bg recovered from class II dimers isolated from living cells. These peptides are derived from intact Ags by proteolysis in endocyti c organelles, where binding to class II dimers also occurs. Whether ge neration of these short peptides typically precedes association with c lass II molecules, or whether class Il molecules initially hind to unf olded proteins or large protein fragments, followed by degradation of the unprotected regions, remains unknown. Here we report the identific ation of an SDS-stable, long-lived, 120-kDa complex composed of two cl ass IT dimers bound to a common large Ag fragment, This complex is pro duced within the endocytic pathway from newly synthesized MHC class II molecules following exposure of the cells to exogenous hers egg lysoz yme. These data suggest that a major pathway of Ag processing involves the initial binding of class LT heterodimers to large protein substra tes upon exposure of regions with suitable motifs, followed by cleavag e and/or trimming of the exposed protein around this bound region. Thi s sequence of events during Ag processing mag provide a partial molecu lar explanation for the immunodominance of certain determinants in pro tein Ags.