Premature cell senescence and T cell receptor-independent activation of CD8+ T cells in Juvenile idiopathic arthritis

Jeffrey A. Dvergsten, Robert G. Mueller, Patricia Griffin, Sameem Abedin, Allyson Pishko, Joshua J. Michel, Margalit E. Rosenkranz, Ann M. Reed, Daniel A. Kietz, Abbe N. Vallejo

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Abstract

Objective CD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA. Methods Blood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor. Results JIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28 nullCD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28 nullCD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone γH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon-γ and interleukin-10. Conclusion These data provide the first evidence of cell senescence, as represented by CD31+CD28null CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR-independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.

Original languageEnglish (US)
Pages (from-to)2201-2210
Number of pages10
JournalArthritis and rheumatism
Volume65
Issue number8
DOIs
StatePublished - Aug 1 2013

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

Dvergsten, J. A., Mueller, R. G., Griffin, P., Abedin, S., Pishko, A., Michel, J. J., Rosenkranz, M. E., Reed, A. M., Kietz, D. A., & Vallejo, A. N. (2013). Premature cell senescence and T cell receptor-independent activation of CD8+ T cells in Juvenile idiopathic arthritis. Arthritis and rheumatism, 65(8), 2201-2210. https://doi.org/10.1002/art.38015