Gender-Biased Regulation of Human IL-17-Producing Cells in Vitro by Peptides Corresponding to Distinct HLA-DRB 1 Allele-Coded Sequences

Abstract

Susceptibility to rheumatoid arthritis (RA) is associated with HLA-DRB1 alleles coding a 5-amino acid sequence motif called the shared epitope (SE). To explore the potential mechanisms that lead to RA susceptibility, we analyze the in vitro effect of peptides bearing different HLA-DR4 sequences on human peripheral blood-derived cells. Three 15-mer peptides were used: 65-79*0401 (an HLA-DRB1*04:01-coded sequence carrying the SE motif, QKRAA); 65-79*0402 (an HLA-DRB1*04:02-coded sequence carrying a SE-negative motif, DERAA); 65-79*0403 (an HLA-DRB1*04:03-coded sequence carrying a SE-negative motif, QRRAE). We found that CD4 TH17 cells are regulated by peptide treatment with gender bias. In male-derived T cells, all peptide treatments significantly reduced TH17 cell differentiation in vitro when compared to no peptide treatment, and to female samples. TH17 differentiation in samples not treated with peptides, either in the presence or absence of TH17-polarizing cytokines, was higher in males than in females; however, in unfractionated PBMC after treatment with TH17 polarizing cytokines, IL-17A positive cells were more abundant in females than in males. In addition, SE-positive females showed a significantly higher percentage of IL-17A-positive cells compared to SE-negative females. In conclusion, donor's SE status and gender may both influence TH17 immune polarization.