title: Premature cell senescence and T cell receptor-independent activation of CD8+ T cells in juvenile idiopathic arthritis.
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(null) CD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28(null) CD8+ 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.
  
  
  CONCLUSIONS
  These data provide the first evidence of cell senescence, as represented by CD31+CD28(null) 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.
authors.affiliation: Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Dvergsten
authors.forename: Robert G
authors.initials: RG
authors.lastname: Mueller
authors.forename: Patricia
authors.initials: P
authors.lastname: Griffin
authors.forename: Sameem
authors.initials: S
authors.lastname: Abedin
authors.forename: Allyson
authors.initials: A
authors.lastname: Pishko
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Michel
authors.forename: Margalit E
authors.initials: ME
authors.lastname: Rosenkranz
authors.forename: Ann M
authors.initials: AM
authors.lastname: Reed
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kietz
authors.forename: Abbe N
authors.initials: AN
authors.lastname: Vallejo
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000276:immunology* / Q000473:pathology; D018106:CD28 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D016615:Telomere / Q000473:pathology; D013997:Time Factors
chemical_list: D018106:CD28 Antigens; D019941:Cyclin-Dependent Kinase Inhibitor p16; C468783:H2AX protein, human; D006657:Histones; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011948:Receptors, Antigen, T-Cell