Specificity, frequency, and phenotype of citrullinated-specific T cells vary with disease activity in rheumatoid arthritis

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Abstract

In rheumatoid arthritis (RA), CD4+ T cells specific for citrullinated antigens (cit-antigens) are key drivers of disease, but knowledge about epitopes and phenotypes remains limited. We characterized the frequency and phenotype of cit-specific CD4+ T cells in peripheral blood using HLA class II tetramers combined with computational analysis of phenotypic clusters to simultaneously detect peptides derived from 5 cit-antigens (aggrecan, vimentin, fibrinogen, cartilage intermediate layer protein, and α-enolase) previously implicated in RA pathogenesis. In a cross-sectional cohort, cit-aggrecan–, cit-vimentin–, and cit-fibrinogen–specific T cells were more frequent in participants with RA than healthy volunteers, associated with active disease, and had Th1-like and stem-like lineages in RA. In a longitudinal cohort investigating response to therapy, the frequency of cit-aggrecan–, cit-vimentin–, and cit-fibrinogen–specific CD4+ T cells was significantly higher at baseline and further elevated in responders. Furthermore, the frequency of cit-specific Th1-like cells in responders decreased over time. In contrast, the frequency of Th1-like cells in non-responders increased over time. Collectively, these findings demonstrate that cit-specific CD4+ T cells are expanded in RA and target a broad number of antigens across a breadth of phenotypes. Furthermore, the predominant antigen specificities associate with disease activity and exhibit dynamic changes in phenotype that reflect response to therapy.

Authors

Cliff Rims, Hannah A. DeBerg, Sylvia E. Posso, Virginia S. Muir, Hannes Uchtenhagen, Anne M. Hocking, Heather Bukiri, Jeffrey Carlin, Bernard Ng, Peter S. Linsley, Eddie A. James, Jane H. Buckner