Dendritic cells (DCs) are the major antigen presenting cells of the immune system, bridging the innate and adaptive immune response. DCs undergo a context-dependent maturation program that enables presentation to T cells. During inflammation, mature DCs express costimulatory molecules and activate T cells, whereas during homeostasis, mature DCs promote tolerance through maintenance of T regulatory cells. Although this process is critical to immune tolerance, the molecular mechanisms that enable context-dependent maturation remain poorly defined.
Our lab recently identified the transcription factor ETV3 as a regulator of homeostatic DC maturation; DC-specific deletion of ETV3 in mice lead to spontaneous partial immunogenic maturation of DCs and systemic autoimmunity. ETV3-deficient DCs aberrantly expressed the costimulatory molecule OX40L, which is normally restricted to immunogenically mature DCs. Both ETV3 and TNFSF4 (the gene encoding OX40L) are strongly linked to systemic lupus erythematosus (SLE) by genome-wide association studies, suggesting that ETV3-mediated antagonism of OX40L expression in mature DC may be relevant for systemic autoimmunity.
We aim to define the underlying molecular mechanisms through which ETV3 controls OX40L expression and contributes to autoimmunity in ETV3-deficient mice. Our working model posits that ETV3 directly binds to regulatory elements of Tnfsf4 and represses its expression, likely through competition with other transcription factors. We have identified a candidate DC-specific regulatory region of Tnfsf4 that may serve as a target of ETV3-mediated repression in homeostatic DC maturation, and will present its further characterization. The results may help explain how immunogenic programs are appropriately restrained during tolerogenic DC maturation while remaining poised for rapid induction upon inflammatory stimulation and/or in autoimmunity.