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Expansion of Peripheral CD8+ CD28– T Cells in Response to Epstein-Barr Virus in Patients with Rheumatoid Arthritis
TATJANA KLATT, QIN OUYANG, THOMAS FLAD, INA KOETTER, HANS-JÖRG BÜHRING, HUBERT KALBACHER, GRAHAM PAWELEC, and CLAUDIA A. MÜLLER
ABSTRACT. 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. Conclusion. 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. (J Rheumatol 2005; 32:239-51) Key Indexing Terms:
EPSTEIN-BARR VIRUS-SPECIFIC T CELLS
From the Section for Transplantation-Immunology and Immunohematology; Department II of Internal Medicine, University Clinics, Tuebingen; and the Institute of Physiological Chemistry, University of Tuebingen, Tuebingen, Germany. Supported in part by a grant from the Federal Ministry of Education and Research (Fö. 01KS9602) and the Interdisciplinary Center of Clinical Research (IZKF), project II C5, Med. Faculty, Univ. Tuebingen, Germany; and by grant PA 361/7-1 from the German Research Foundation (DFG). T. Klatt, MD; Q. Ouyang, MD; T. Flad, PhD; G. Pawelec, PhD; C.A. Müller, MD, Section for Transplantation–Immunology and Immunohematology; I. Koetter, MD; H.J. Bühring, PhD, Department II of Internal Medicine, University Clinics, Tuebingen; H. Kalbacher, PhD, Center of Medical and Natural Sciences, Institute of Physiological Chemistry, University of Tuebingen. Dr. Klatt and Dr. Ouyang contributed equally to this work. Address reprint requests to Prof. C.A. Müller, Section for Transplantation–Immunology and Immunohematology, ZMF, Waldhoernlestrasse 22, 72072 Tuebingen, Germany. E-mail: claudia.mueller@uni-tuebingen.de Submitted March 26, 2004; revision accepted September 29, 2004. |