Molecular aspects of IL-13 up-regulation by CD8+ T cells from systemic sclerosis patients (BA3P.132)

Systemic sclerosis (SSc), an incurable connective tissue disease, is characterized by vascular damage, inflammation and fibrosis. T cells are important in pathogenesis and produce cytokines that contribute to the induction of fibrosis. We found that dysregulated production of the profibrotic cytokine IL-13 by effector CD8+ T cells is associated with more severe skin thickening in SSc and defects in the molecular control of IL-13 production, such as increased expression of the Th2-specific transcription factor GATA-3. Silencing of GATA-3 by siRNA blocks IL-13 production in CD8+ T cells, demonstrating a causal relation¬ship between GATA-3 and IL-13. GATA-3 is also highly expressed by CD8+ T cells in lesions of patients where it may be associated with overproduction of IL-13. Th1-specific T-bet induces IFN-γ production and inhibits Th2 cytokines, including IL-13, by antagonizing GATA-3 expression and/or function. Here we show that CD8+ T cells from patient blood express high levels of IL-13 and GATA-3 but levels of IFN-γ and T-bet similar to controls. We also found that the interaction between T-bet and GATA-3 in SSc CD8+ T cells is weaker allowing more GATA-3 to bind to the IL-13 promoter and induce its expression. We conclude that increased IL-13 expression by SSc CD8+ T cells results, at least in part, from reduced down-regulation of GATA-3 by T-bet. Our new insights will establish novel biomarkers of immune dysfunction in SSc patients that can be used as therapeutic targets.