ARTHRITIS & RHEUMATISM Vol. 63, No. 11, November 2011, pp 3284–3293 DOI 10.1002/art.30570 © 2011, American College of Rheumatology The Response of T Cells to Interleukin-6 Is Differentially Regulated by the Microenvironment of the Rheumatoid Synovial Fluid and Tissue Ester Hidalgo, 1 Sarah J. Essex, 1 Lorraine Yeo, 1 S. John Curnow, 1 Andrew Filer, 2 Mark S. Cooper, 1 Andrew M. Thomas, 3 Helen M. McGettrick, 1 Michael Salmon, 1 Christopher D. Buckley, 2 Karim Raza, 2 and Dagmar Scheel-Toellner 1 Objective. Interleukin-6 (IL-6) is a proinflamma- tory cytokine with regulatory effects on the survival and differentiation of T cells. It exerts its biologic function in 2 ways: by directly binding to the IL-6 receptor (IL-6R; CD126) or via trans-signaling, in which soluble IL-6R/ IL-6 complexes bind to the signaling component CD130. This study was undertaken to assess the expression and regulation of CD126 and CD130 and determine how these affect the response of CD4 T cells to IL-6 in the joints of patients with rheumatoid arthritis (RA). Methods. Flow cytometry and immunofluores- cence microscopy were used to determine the expres- sion, function, and regulation of CD126 and CD130 in CD4 T cells from the peripheral blood (PB), synovial fluid (SF), and synovial tissue of RA patients. Results. Compared to the findings in RA PB, CD4 T cells in the SF and synovial tissue expressed low levels of CD126. In contrast, whereas CD4 T cell expression of CD130 was minimal in the SF, its level in the synovial tissue was high. Consistent with this phe- notype, synovial tissue T cells responded to trans- signaling by soluble IL-6R/IL-6 complexes, whereas no response was evident in CD4 T cells from the SF. Down-regulation of both receptor components in SF T cells could be explained by exposure to high levels of IL-6. Increased levels of CD130 messenger RNA and protein in synovial tissue CD4 T cells suggested that CD130 is up-regulated locally. Among a range of cyto- kines tested, only IL-10 induced CD130 expression in T cells. Conclusion. The inflamed microenvironment in the synovial tissue maintains responsiveness to IL-6 trans-signaling through the up-regulation of CD130 expression in CD4 T cells, and this process may be driven by IL-10. The importance of interleukin-6 (IL-6) in the pathologic development of rheumatoid arthritis (RA) is underlined by extensive data on the clinical effectiveness of tocilizumab, an anti–IL-6 receptor (anti–IL-6R) blocking antibody (1,2). IL-6 is found in the peripheral blood (PB) and, at higher levels, in the synovial fluid (SF) of RA patients (3). The levels of IL-6 correlate with disease activity (4), and it drives the acute-phase re- sponse by inducing hepatic expression of C-reactive protein (CRP) and related factors (5). Among its range of activities in the human body, IL-6 is an important regulator of T cell differentiation and survival. It mod- ulates the balance between regulatory T cells (Treg cells) and proinflammatory IL-17–producing T cells (6,7). The receptor for IL-6 consists of 2 independently regulated membrane proteins, the IL-6–specific compo- Supported by Arthritis Research UK through a program grant to Drs. Salmon and Buckley (grant 16390), equipment grants to Drs. Raza and Scheel-Toellner (grants 18198 and 17767), and a Career Development Fellowship and a Career Progression Fellowship to Dr. Scheel-Toellner (grants 16191 and 19394, respectively) and by a European Union Sixth Framework Programme PhD studentship (Marie Curie Actions Initial Training Network Trifid award to Ms Hi- dalgo). 1 Ester Hidalgo, BSc, Sarah J. Essex, PhD, Lorraine Yeo, MPhil, S. John Curnow, PhD, Mark S. Cooper, PhD, MRCP, Helen M. McGettrick, PhD, Michael Salmon, PhD, FRCPath, Dagmar Scheel- Toellner, PhD: University of Birmingham, Birmingham, UK; 2 Andrew Filer, MBChB, PhD, MRCP, Christopher D. Buckley, PhD, FRCP, Karim Raza, PhD, FRCP: University of Birmingham and the Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK; 3 An- drew M. Thomas, MBBS, FRCS: The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK. Dr. Raza has received speaking fees and/or honoraria from UCB (less than $10,000). Address correspondence to Dagmar Scheel-Toellner, PhD, Rheumatology Research Group, MRC Centre for Immune Regula- tion, School of Immunity and Infection, College of Medical and Den- tal Sciences, University of Birmingham, Birmingham B15 2TT, UK. E-mail: d.scheel@bham.ac.uk. Submitted for publication September 2, 2010; accepted in revised form July 21, 2011. 3284