title: Tumor necrosis factor-costimulated T lymphocytes from patients with systemic sclerosis trigger collagen production in fibroblasts.
abstract: OBJECTIVE
  The role of tumor necrosis factor (TNF) in systemic sclerosis (SSc) remains controversial. The present study was undertaken to investigate the influence of TNF receptor (TNFR)-costimulated lymphocytes on collagen expression in fibroblasts.
  
  
  METHODS
  TNFR expression on mononuclear cells from the dermis and blood of SSc patients was assessed by flow cytometry. Peripheral blood CD3+ lymphocytes were activated with CD3/CD28 beads and costimulated with TNFR-selective variants. Expression of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), IL-10, and IL-13 was detected by enzyme-linked immunosorbent assay or quantitative reverse transcription-polymerase chain reaction. Healthy fibroblasts were incubated with conditioned media from TNFR-costimulated T lymphocytes, and type I collagen expression was quantified.
  
  
  RESULTS
  TNFRI and TNFRII were up-regulated on dermal T lymphocytes from patients with diffuse cutaneous SSc. TNFRII expression correlated with skin thickening. After CD3/CD28 activation, peripheral blood lymphocytes from SSc patients produced more IL-6, sIL-6R, and IL-13 compared to healthy lymphocytes. Costimulation with TNFRI-selective ligands and soluble TNF further increased IL-6 expression, whereas costimulation with TNFRII led to greater release of sIL-6R. IL-10 expression, which normally occurs after TNFRII costimulation, was impaired in SSc T cells. Supernatants of TNF-costimulated SSc lymphocytes induced higher type I collagen expression in fibroblasts, which was partially reversible by dual inhibition of IL-6 and IL-13. Expression of TNFR and IL-6 in the dermis was reversible in a patient who received lymphoablative therapy prior to autologous hematopoietic stem cell transplantation.
  
  
  CONCLUSIONS
  TNF-costimulated T lymphocytes from SSc patients have a propensity to secrete profibrotic cytokines, while the ability to produce IL-10 is weakened. These results suggest that T lymphocytes in SSc support fibrosis, but might lack the capacity to resolve inflammation.
authors.affiliation: Newcastle University, Newcastle upon Tyne, UK. Thomas.Huegle@unibas.ch
authors.forename: Thomas
authors.initials: T
authors.lastname: Hügle
authors.forename: Steven
authors.initials: S
authors.lastname: O'Reilly
authors.forename: Rachel
authors.initials: R
authors.lastname: Simpson
authors.forename: Marina D
authors.initials: MD
authors.lastname: Kraaij
authors.forename: Venetia
authors.initials: V
authors.lastname: Bigley
authors.forename: Matthew
authors.initials: M
authors.lastname: Collin
authors.forename: Anja
authors.initials: A
authors.lastname: Krippner-Heidenreich
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
mesh_terms: D000328:Adult; D003094:Collagen / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018793:Interleukin-13; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen