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CD4+ Memory Stem T Cells Recognizing Citrullinated Epitopes Are Expanded in Patients With Rheumatoid Arthritis and Sensitive to Tumor Necrosis Factor Blockade
Author(s) -
Cianciotti Beatrice C.,
Ruggiero Eliana,
Campochiaro Corrado,
Oliveira Giacomo,
Magnani Zulma I.,
Baldini Mattia,
Doglio Matteo,
Tassara Michela,
Manfredi Angelo A.,
Baldissera Elena,
Ciceri Fabio,
Cieri Nicoletta,
Bonini Chiara
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41157
Subject(s) - immunology , tumor necrosis factor alpha , flow cytometry , vimentin , rheumatoid factor , epitope , antibody , t cell , medicine , cancer research , biology , immunohistochemistry , immune system
Objective Memory stem T (Tscm) cells are long‐lived, self‐renewing T cells that play a relevant role in immunologic memory. This study was undertaken to investigate whether Tscm cells accumulate in rheumatoid arthritis ( RA ). Methods The polarization and differentiation profiles of circulating T cells were assessed by flow cytometry. Antigen‐specific T cells were characterized by staining with major histocompatibility complex class II tetramers. The T cell receptor ( TCR ) repertoire was analyzed by high‐throughput sequencing using an unbiased RNA ‐based approach in CD 4+ T cell subpopulations sorted by fluorescence‐activated cell sorting. Results We analyzed the dynamics of circulating Tscm cells (identified as CD 45 RA + CD 62L+ CD 95+ T cells) by flow cytometry in 27 RA patients, 16 of whom were also studied during treatment with the anti–tumor necrosis factor (anti‐ TNF ) agent etanercept. Age‐matched healthy donors were used as controls. CD 4+ Tscm cells were selectively and significantly expanded in RA patients in terms of frequency and absolute numbers, and significantly contracted upon anti‐ TNF treatment. Expanded CD 4+ Tscm cells displayed a prevalent Th17 phenotype and a skewed TCR repertoire in RA patients, with the 10 most abundant clones representing up to 53.7% of the detected sequences. CD 4+ lymphocytes specific for a citrullinated vimentin (Cit‐vimentin) epitope were expanded in RA patients with active disease. Tscm cells accounted for a large fraction of Cit‐vimentin–specific CD 4+ cells. Conclusion Our results indicate that Tscm cells, including expanded clones specific for relevant autoantigens, accumulate in RA patients not exposed to biologic agents, and might be involved in the natural history of the disease. Further analysis of Tscm cell dynamics in autoimmune disorders may have implications for the design and efficacy assessment of innovative therapies.