Rheumatoid arthritis occurs most often in people who express HLA-DR molecules containing a five aa “shared epitope” in the β chain. These MHCII molecules preferentially bind citrullinated peptides formed by posttranslational modification of arginine. Citrullinated peptide:HLA-DR complexes may act as arthritis-initiating neo-antigens for CD4+ T cells. Here, we used fluorophore-conjugated HLA-DR tetramers containing citrullinated peptides from human cartilage intermediate layer protein, fibrinogen, vimentin, or enolase 1 to track cognate CD4+ T cells. Immunization of HLA-DR transgenic mice with citrullinated peptides from vimentin or enolase 1 failed to cause any expansion of tetramer-binding cells, whereas immunization with citrullinated peptides from cartilage intermediate layer protein or fibrinogen elicited some expansion. The expanded tetramer-binding populations, however, had lower T helper 1 and higher regulatory T cell frequencies than populations elicited by viral peptides. These results indicate that HLA-DR–bound citrullinated peptides are not neo-antigens and induce varying degrees of immune tolerance that could pose a barrier to rheumatoid arthritis.
The CD4+ T cell repertoire specific for citrullinated peptides shows evidence of immune tolerance
Disclosures: The authors declare no competing interests exist.
- Award Id(s): P01 AI35962,R01 AI027998,T32 HL007741
- Award Id(s): 889570
Matthew K. McElwee, Thamotharampillai Dileepan, Shawn A. Mahmud, Marc K. Jenkins; The CD4+ T cell repertoire specific for citrullinated peptides shows evidence of immune tolerance. J Exp Med 4 December 2023; 220 (12): e20230209. doi: https://doi.org/10.1084/jem.20230209
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