Tumor necrosis factor–costimulated T lymphocytes from patients with systemic sclerosis trigger collagen production in fibroblasts

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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. Conclusion 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.

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