POLYMORPHISM IN THE BETA-CHAIN OF IA(Q) VERSUS IA(P) INFLUENCES PRESENTATION OF PROTEIN BUT NOT PEPTIDE ANTIGENS

T cells play a critical role in the development of collagen-induced ar thritis (CIA). Immunization with heterologous (chick) type II collagen (cII) results in chronic inflammation with progressive damage to the joints. The expression of specific MHC Class II alpha beta dimers, inc luding IA(q), is critical to induction of disease. The alpha chains of IA(q) and IA(p) are identical in sequence. The IA(q) and IA(p) beta c hains differ by only four amino acid residues: 85, 86, 88, and 89. How ever, mice of the H-2(p) haplotype are not susceptible tee CIA. To exa mine the impact of these structural differences in IA molecules on T c ell Ag recognition, we studied presentation of cII peptides and denatu red cII by APCs obtained from H-2(q) and H-2(p) mice. We also assessed presentation of ovalbumin, myelin basic protein (MBP), and MBP peptid es by these APC populations. H-2(q) APCs presented both peptides and p roteins to our T cell hybrids. In contrast, APCs obtained from H-2(p) mice presented peptides, but were defective in the processing and/or p resentation of protein Ags. We then altered pairs of the residues in I A(q) to those found in IA(p) using site-directed mutagenesis and trans fected these constructs into M 12.C3 B cells. All transfectants were a ble to present peptides, but those expressing IA(p) were unable to pre sent protein Ags. The use of transfectants expressing hybrid molecules (residues 85 and 86 from IA(p), 88 and 89 from IA(q), or vice versa) allowed us to localize the region responsible for this defect to resid ues 85 and 86 of the beta chain. The presence of IA(p) residues (glu a nd thr versus gly and val in IA(q)) at these sites severely compromise d the capacity for protein presentation. Resistance to CIA in H-2(p) h aplotype mice may be a reflection of the limited repertoire of epitope s to which these mice can respond relative to susceptible H-2(q) mice. (C) 1995 Academic Press, Inc.