Research article Skewed distribution of proinflammatory CD4 + CD28 null T cells in rheumatoid arthritis

Expanded populations of CD4+ T cells lacking the costimulatory molecule CD28 (CD4+CD28null T cells) have been reported in several inflammatory disorders. In rheumatoid arthritis, increased frequencies of CD4+CD28null T cells in peripheral blood have previously been associated with extraarticular manifestations and human cytomegalovirus (HCMV) infection, but their presence in and contribution to joint manifestations is not clear. In the present article we investigated the distribution of CD4+CD28null T cells in the synovial membrane, synovial fluid and peripheral blood of RA patients, and analysed the association with erosive disease and anticitrullinated protein antibodies. CD4+CD28null T cells were infrequent in the synovial membrane and synovial fluid, despite significant frequencies in the circulation. Strikingly, the dominant TCR-Vβ subsets of CD4+CD28null T cells in peripheral blood were often absent in synovial fluid. CD4+CD28null T cells in blood and synovial fluid showed specificity for HCMV antigens, and their presence was clearly associated with HCMV seropositivity but not with anti-citrullinated protein antibodies in the serum or synovial fluid, nor with erosive disease. Together these data imply a primary role for CD4+CD28null T cells in manifestations elsewhere than in the joints of patients with HCMV-seropositive rheumatoid arthritis.

[1]  D. Fox,et al.  Cells of the synovium in rheumatoid arthritis. T lymphocytes , 2007, Arthritis research & therapy.

[2]  J. Zack,et al.  CD4 Expression on Activated NK Cells: Ligation of CD4 Induces Cytokine Expression and Cell Migration1 , 2006, The Journal of Immunology.

[3]  M. Uffmann,et al.  Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. , 2006, Rheumatology.

[4]  A. Rebuzzi,et al.  Modulation of CD4+CD28null T Lymphocytes by Tumor Necrosis Factor-&agr; Blockade in Patients With Unstable Angina , 2006, Circulation.

[5]  Arne N. Akbar,et al.  Cytomegalovirus-Specific CD4+ T Cells in Healthy Carriers Are Continuously Driven to Replicative Exhaustion1 , 2005, The Journal of Immunology.

[6]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[7]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[8]  E. Matteson,et al.  Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis , 2005 .

[9]  H. Ljunggren,et al.  2B4/CD48-Mediated Regulation of Lymphocyte Activation and Function 1 , 2005, The Journal of Immunology.

[10]  R. Frye,et al.  Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study , 2005, Arthritis research & therapy.

[11]  L. Klareskog,et al.  Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression , 2005, Annals of the rheumatic diseases.

[12]  C. Söderberg-Nauclér,et al.  Human Cytomegalovirus Infection of Endothelial Cells Triggers Platelet Adhesion and Aggregation , 2005, Journal of Virology.

[13]  T. Ottenhoff,et al.  Phenotypic and Functional Characterization of CD4 T Cells Expressing Killer Ig-Like Receptors1 , 2004, The Journal of Immunology.

[14]  B. Machaliński,et al.  Therapy with infliximab decreases the CD4+CD28− T cell compartment in peripheral blood in patients with rheumatoid arthritis , 2004, Rheumatology International.

[15]  R. V. van Vollenhoven,et al.  CD28nullCD4+ T Cells – Characterization of an Effector Memory T‐Cell Population in Patients with Rheumatoid Arthritis , 2004, Scandinavian journal of immunology.

[16]  C. Söderberg-Nauclér,et al.  Recognition of cytomegalovirus clinical isolate antigens by sera from cytomegalovirus‐negative blood donors , 2004, Transfusion.

[17]  A. Giordano,et al.  CD4+CD28− T Lymphocytes Contribute to Early Atherosclerotic Damage in Rheumatoid Arthritis Patients , 2004, Circulation.

[18]  R. Ward,et al.  Activated Primary and Memory CD8 T Cells Migrate to Nonlymphoid Tissues Regardless of Site of Activation or Tissue of Origin1 , 2004, The Journal of Immunology.

[19]  B. Machaliński,et al.  The expansion of CD4+CD28- T cells in patients with rheumatoid arthritis , 2003, Arthritis research & therapy.

[20]  A. Vallejo,et al.  CD28 loss in senescent CD4+ T cells: reversal by interleukin-12 stimulation. , 2003, Blood.

[21]  Andrew J. McMichael,et al.  Clonal Selection, Clonal Senescence, and Clonal Succession: The Evolution of the T Cell Response to Infection with a Persistent Virus1 , 2002, The Journal of Immunology.

[22]  R. Frye,et al.  T-Cell–Mediated Lysis of Endothelial Cells in Acute Coronary Syndromes , 2002, Circulation.

[23]  A. Vallejo,et al.  Down-Regulation of CD28 Expression by TNF-α1 , 2001, The Journal of Immunology.

[24]  R. Frye,et al.  Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. , 2000, Circulation.

[25]  M. Hooper,et al.  Cytomegalovirus seropositivity is associated with the expansion of CD4+CD28- and CD8+CD28- T cells in rheumatoid arthritis. , 1999, The Journal of rheumatology.

[26]  P. Miossec,et al.  Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. , 1999, Arthritis and rheumatism.

[27]  F. Breedveld,et al.  Poor expression of T cell-derived cytokines and activation and proliferation markers in early rheumatoid synovial tissue. , 1998, Clinical immunology and immunopathology.

[28]  D. Schaid,et al.  Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. , 1997, Arthritis and rheumatism.

[29]  C. Weyand,et al.  The Repertoire of CD4+ CD28− T Cells in Rheumatoid Arthritis , 1996, Molecular medicine.

[30]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[31]  Harun Tuğcu,et al.  Detection of cytomegalovirus and Helicobacter pylori DNA in arterial walls with grade III atherosclerosis by PCR. , 2006, Polish journal of microbiology.

[32]  Eric O Long,et al.  Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. , 2006, Blood.

[33]  Cynthia S Crowson,et al.  Prognostic markers of radiographic progression in early rheumatoid arthritis. , 2004, Arthritis and rheumatism.

[34]  C. Weyand,et al.  CD4+,CD28- T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. , 2001, Arthritis and rheumatism.

[35]  D. Elewaut,et al.  Needle Arthroscopy of the Knee with Synovial Biopsy Sampling: Technical Experience in 150 Patients , 1999, Clinical Rheumatology.