Endogenous activation of adaptive immunity: Tenascin-C drives interleukin-17 synthesis in murine arthritic joint disease

Objective Rheumatoid arthritis is characterized by persistent synovial inflammation and progressive joint destruction, which are mediated by innate and adaptive immune responses. Cytokine blockade successfully treats some patient subsets; however, similar to 50% do not respond to this approach. Targeting of pathogenic T lymphocytes is emerging as an effective alternative/complementary therapeutic strategy, yet the factors that control T cell activation in joint disease are not well understood. Tenascin-C is an arthritogenic extracellular matrix glycoprotein that is not expressed in healthy synovium but is elevated in the rheumatoid joint, where high levels are produced by myeloid cells. Among these cells, tenascin-C expression is most highly induced in activated dendritic cells (DCs). The aim of this study was to examine the role of tenascin-C in this cell type. Methods We systematically compared the phenotype of DCs isolated from wild-type mice or mice with a targeted deletion of tenascin-C by assessing cell maturation, cytokine synthesis, and T cell polarization. Results Dendritic cells derived from tenascin-Cnull mice exhibited no defects in maturation; induction of the class II major histocompatibility complex and the costimulatory molecules CD40 and CD86 was unimpaired. Dendritic cells that did not express tenascin-C, however, produced lower levels of inflammatory cytokines than did cells from wild-type mice and exhibited specific defects in Th17 cell polarization. Moreover, tenascin-Cnull mice displayed ablated levels of interleukin-17 in the joint during experimental arthritis. Conclusion These data demonstrate that tenascin-C is important in DC-mediated polarization of Th17 lymphocytes during inflammation and suggest a key role for this endogenous danger signal in driving adaptive immunity in erosive joint disease.