Sox5 and Th17 cell differentiation

Sox (SRY-related high-mobility-group (HMG)-box) transcription factors, which are comprised of 20 genes containing a conserved HMG DNA-binding domain, are divided into 8 groups (from A to H) according to structural homologies [reviewed in 1-2]. SoxC group, which is composed of Sox4, Sox11, and Sox12, has a HMG box domain and a transactivation domain and plays important roles in the development of heart, nerve system, kidney, and pancreas. SoxD group, which is composed of Sox5, Sox6, and Sox13, has a HMG box domain in C-terminal half and group-specific coiled-coil domain(s) in N-terminal half. SoxD proteins interact with each other through their coiled-coil domain and their activity is likely to be influenced by other molecules with which they interact. Sox5 and Sox6 are paralogous genes highly expressed in spermatids, neurons, oligodendrocytes, and chondrocytes, and are indispensable for chondrogenesis. Regarding the roles of Sox family genes in T cell immunity, it has been demonstrated that Sox4 suppresses GATA3 function and thereby inhibits Th2 cell-mediated inflammation [reviewed in 3]. On the other hand, Sox13 plays a critical role in the development of γδ T cell receptor+ thymocytes and Sox13, together with Sox4, induces the differentiation of IL-17-producing γδ T cells (Tγδ17 cells) through the induction of orphan nuclear receptor RORγt [3]. Sox4 is also expressed in αβ T cells; however, Sox4 is not essential for the differentiation of IL-17-producing αβ T cells (Th17 cells) [3], which are involved not only in the host defense against extracellular pathogens but also in the pathogenesis of autoimmune diseases [4]. Because RORγt, which is encoded by Rorc gene, plays a central role in the differentiation of Th17 cells as well as Tγδ17 cells [4], it is suggested that the involvement of Sox transcription factors in RORγt induction seems different between Th17 cells and Tγδ17 cells. It is well established that IL-6and/or IL-21mediated Stat3 activation is indispensable for the induction of RORγt during Th17 cell differentiation. Stat3 binds to intron 1 of Rorc gene and induces chromatin remodeling of the locus. In addition, Stat3 activation results in the induction of many genes implicated in Th17 cell differentiation such as Nfkbiz, Rora, Batf, Irf4, Ahr, Maf, and HIF-1α (Figure 1) [4]. Among these genes, HIF1 has been shown to activate Rorc promoter. However, the downstream targets of Stat3 for RORγt induction in Th17 cells have not been fully understood. To identify the downstream pathway of IL-6-Stat3 signaling for Th17 cell differentiation, we have performed DNA microarray analysis of IL-6-stimulated CD4+ T cells. We found that c-Maf and a novel isoform of Sox5 (named Sox5t) were highly induced in IL-6-stimulated CD4+ T cells and that Editorial