a9b1 Integrin-Mediated Signaling Serves as an Intrinsic Regulator of Pathogenic Th17 Cell Generation

The interaction between matricellular proteins such as tenascin-C (TN-C) and osteopontin (OPN) and integrins has been implicated in the pathology of rheumatoid arthritis in which Th17 cells are recognized as primary pathogenic cells. The differentiation of Th17 cells is tightly regulated by cytokines derived from APCs, receiving various signals including TLR stimuli. In this study, we used a collagen-induced arthritis model and found that increased numbers of a 9 integrin-positive conventional dendritic cells and macrophage were detectable in the draining lymph node (dLN) shortly following first immunization, and these cells produced both TN-C and OPN, ligands for a 9 integrin. a 9 integrin-mediated signaling, induced by TN-C and OPN, promoted the production of Th17-related cytokines by conventional dendritic cells and macrophages in synergy with TLR2 and 4 signaling. This led to the Th17 cell differentiation and arthritis development. Moreover, Th17 cells generated under blocking of a 9 integrin-mediated signaling showed low level of CCR6 expression and impaired migration ability toward CCL20. Thus, we have identified a 9 integrin-mediated signaling by TN-C and OPN as a novel intrinsic regulator of pathogenic Th17 cell generation that contributes to the development of rheumatoid arthritis. D uring inflammatory responses, APCs at the draining lymph node (dLN) play a critical role in the differentiation of naive CD4 + T cells into several types of Th subset cells by producing cytokines. It has been well known that several cytokines, including IL-6 and IL-23, drive the generation of IL-17–producing CD4 + Th cells (Th17) cells, whereas IL-12 favors the generation of IFN-g–producing CD4 + Th cells (Th1) (1, 2). The production of Th1-or Th17-polarizing cytokines by den-dritic cells (DCs) and macrophages at the dLN is triggered and regulated by TLR-, CD40-, and C5a receptor-mediated signaling (3–7). Following recognition of different types of pathogen-associated molecular patterns through specific TLRs, APCs produce several types of cytokine, which results in the differentiation from naive CD4 + T cells into distinct Th cell subset such as Th1 or Th17 (1, 8, 9). Although recent study has revealed that a specific pathogen such as segmented filamentous bacteria can induce the generation of Th17 cells (10), APCs often produce both Th1-and Th17-polarizing cytokines at the same time following stimulation with certain TLR ligand (11–14), suggesting that other complex mechanisms might be involved for the decision of Th1 and/or Th17 development in vivo. It has been demonstrated that matricellular proteins such as tenascin-C (TN-C) …