T cell recognition of human pre-proinsulin peptides depends on the polymorphism at HLA DQ locus: a study using HLA DQ8 and DQ6 transgenic mice.
HLA DQ8 (DQ A1*0301/DQB1*0302) molecule is implicated in the susceptibility to insulin dependent diabetes mellitus whereas, HLA DQ6 (DQ A1*0103/DQB1*0601) molecule may have a protective effect. In this study we used mice transgenic to HLA DQ8 and HLA-DQ6 to elucidate the T cell determinants on a putative islet cell target antigen, insulin. These mice do not express endogenous mouse class II heterodimers on cell surface. Using overlapping synthetic peptides spanning the complete sequence of huma pre-proinsulin, we identified the sequences recognized by T cells in DQ8 transgenic mice and compared these to those in DQ6 transgenic mice. We observed a differential pattern of recognition of epitopes 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 immunodominant 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-reacted to the mouse pre-proinsulin sequence 1-24. The T cell response were specifically inhibited using anti-CD4 and anti-DQ8 monoclonal antibodies. This cross-recognition of self sequences raises the possibility of modulation of experimental diabetes using this peptide.
Raju
R
R
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Munn
S R
SR
David
C S
CS
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007328:Insulin; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D011110:Polymorphism, Genetic; D011384:Proinsulin / Q000276:immunology*; D011498:Protein Precursors / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C063831:HLA-DQ6 antigen; C109756:HLA-DQ8 antigen; D007328:Insulin; D010455:Peptides; D011498:Protein Precursors; C013737:preproinsulin; D011384:Proinsulin