title: Expansion of peripheral CD8+ CD28- T cells in response to Epstein-Barr virus in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  To investigate control of Epstein-Barr virus (EBV) infection in rheumatoid arthritis (RA) by comparing the frequency phenotypes and function of peripheral CD8+ EBV-peptide antigen-specific T cells in patients with RA and healthy longterm carriers of EBV.
  
  
  METHODS
  The frequency of interferon-g (IFN-g)-producing HLA-A2 or HLA-B8-restricted EBV-reactive CD8+ T cells in peripheral blood mononuclear cells (PBMC) from 49 RA patients and 26 healthy EBV carriers was evaluated in Elispot assays with 12 lytic/latent peptide epitopes. Direct staining with HLA-peptide tetramers containing 3 of these peptides was performed for comparison. The phenotype and function of these T cells was determined by FACS and cytotoxicity testing.
  
  
  RESULTS
  IFN-g production patterns in Elispot assays revealed that EBV-specific CD8+ T cells were directed predominantly against the lytic epitopes A2/GLC and B8/RAK and to a minor extent to all the other lytic and latent epitopes tested, with no significant differences of the frequencies in patients and controls. However, although similar frequencies of CD8+ T cells stained with A2/GLC or B8/RAK tetramers in both groups, the fraction of A2/GLC or B8/RAK-reactive T cells producing IFN-g in response to specific peptide antigen was significantly lower in RA patients than controls. The A2/GLC or B8/RAK tetramer-positive T cells were also substantially enriched in CD28-CD27- T cells of a late-differentiated phenotype in RA patients but not in controls.
  
  
  CONCLUSIONS
  RA patients show clonal expansion of dysfunctional, terminally differentiated CD8+ EBV-specific T cells in their T cell responses to immunodominant lytic peptide EBV epitopes, which could be a sign of specific impairment of virus-host interactions in RA.
authors.affiliation: Section for Transplantation-Immunology and Immunohematology, University Clinics, Tuebingen, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Klatt
authors.forename: Qin
authors.initials: Q
authors.lastname: Ouyang
authors.forename: Thomas
authors.initials: T
authors.lastname: Flad
authors.forename: Ina
authors.initials: I
authors.lastname: Koetter
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Bühring
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Müller
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015415:Biomarkers / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002452:Cell Count; D002460:Cell Line; D049109:Cell Proliferation; D002999:Clone Cells; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000821:virology
chemical_list: D015415:Biomarkers; D018106:CD28 Antigens; D007371:Interferon-gamma