Tolerance to a self-peptide from the third hypervariable region of HLA DRB1*0401 in rheumatoid arthritis patients and normal subjects.

The third hypervariable region (HV3) of HLA-DRB10401 helps the development of severe rheumatoid arthritis by an unknown mechanism. To test whether the third hypervariable region of HLA-DRB10401 may shape the T cell repertoire, we studied proliferative responses to peptides encompassing the third hypervariable region of seven HLA-DRB1 alleles in normal subjects and patients with rheumatoid arthritis. We found that, in general, there is no tolerance to peptides from the third hypervariable region of self-HLA-DRB1 alleles. However, a peptide from the third hypervariable region of DRB10401 (DRB10401 HV3 peptide) is tolerated in people who express HLA-DRB10401. Indeed, PBMCs from people who express DRB10401 do not proliferate to DRB10401 HV3 peptide. Conversely, people who express DRB11501 respond to DRB10401 HV3 peptide. Finally, people who express both DRB10401 (nonresponder haplotype) and DRB11501 (high responder haplotype) do not respond to DRB1 HV3 peptide, thus demonstrating tolerance. Therefore, the third hypervariable region of HLA-DRB10401 shapes the T cell repertoire.