T-CELL RECOGNITION OF HUMAN PRE-PROINSULIN PEPTIDES DEPENDS ON THE POLYMORPHISM AT HLA DQ LOCUS - A STUDY USING HLA DQ8 AND DQG TRANSGENIC MICE

HLA DQ8 (DQ A10301/DQB1*0302) molecule is implicated in the susceptib ility to insulin dependent diabetes mellitus whereas, HLA DQ6 (DQ A10 103/DQB10601) molecule may have a protective effect. In this study we used mice transgenic to HLA DQ8 and HLA-DQ6 to elucidate the T cell d eterminants on a putative islet cell target antigen, insulin. These mi ce do not express endogenous mouse class II heterodimers on cell surfa ce. Using overlapping synthetic peptides spanning the complete sequenc e of human pre-proinsulin, we identified the sequences recognized by T cells in DQ8 transgenic mice and compared these to those in DQ6 trans genic mice. We observed a differential pattern of recognition of epito pes on human pre-proinsulin (HPI) polypeptide presented by the HLA DQ8 allele as compared to HLA DQ6. The sequences 1-24 and 44-63 were immu nodominant in DQ8 transgenic mice while DQ6 transgenic mice primarily recognized sequences 14-33 and 74-93 of HPI. We found that the immune response generated in HLA DQ8 transgenic mice against HPI 1-24 cross-r eacted to the mouse pre-proinsulin sequence 1-24. The T cell response were specifically inhibited using anti-CD4 and anti-DQ8 monoclonal ant ibodies. This cross-recognition of self sequences raises the possibili ty of modulation of experimental diabetes using this peptide. (C) Amer ican Society for Histocompatibility and Immunogenetics, 1997. Publishe d by Elsevier Science Inc.