II Immunol Res 1990;9:178-189 1990 S. Karger AG, Basel 0257-277X/90/0093-017852.75/0 Interactions between Immunogenic Peptides and HLA-DR Molecules Jonathan B. Rothbard, Robert Busch ImmuLogicPharmaceuticalCorp., Palo Alto, Calif., USA A fundamental characteristic of the verte- brate immune system is its capacity to recog- nize and respond to a wide spectrum of anti- gens. At the present time three different classes of molecules have been shown to bind antigen: (i) the immunoglobulins; (ii) the antigen receptor of T cells, and (iii) the class-I and II major histocompatibility pro- teins. Each set of proteins has evolved a sep- arate mechanism to allow them to interact with a diversity of ligands. The best understood are the antibodies, which generate the greatest diversity of anti- gen-combining sites by a combination of ge- netic rearrangements of the exons encoding the variable, joining, diversity and constant regions during B-cell development [1] and subsequent somatic mutation of the rear- ranged immunoglobulin gene [2]. The anti- gen receptors of T cells are related closely to the immunoglobulins, both in their primary structure and genetic organization. Thei di- verse antigen-combining sites appear to arise from similar genetic rearrangements as for antibodies; however, subsequent somatic mutation has never been detected [3]. The third group of antigen-binding molecules, the class=I and II major histocompatibility proteins, has evolved separately. Even though they both contain domains which re- semble immunoglobulins in their tertiary structure, the antigen-combining site is folded in a distinctly different manner [4]. The proposed site is composed of an eight- stranded I]-pleated sheet supporting two heli- cal segments [5]. The most extraordinary feature of these molecules is that even though the proteins encoded for by the ma- jor histocompatibility complex (MHC) re- present one of the most polymorphic fami- lies of molecules known, the residues form- ing the binding site of any single allele are invariable. Nevertheless, each allele can bind a very large number of diverse peptide se- quences. The capacity of MHC class-II molecules to bind peptide antigens was initially dem- onstrated using equilibrium dialysis [6]. The peptide-MHC class-II complex subse- quently was shown to be sufficiently stable to be isolated using gel filtration [7]. Even though an individual MHC allele was shown to interact with a variety of T-cell determi- nants, binding was selective; not all se- quences were capable of binding, nor did all bind with equal affinity [8]. These studies also revealed that the kinet- ics of the formation and dissociation of the complex were unusual. Both rates were ex- tremely slow, requiring hours, rather than