RESEARCH ARTICLE IRF4-Dependent and IRF4-Independent Pathways Contribute to DC Dysfunction in

Interferon Regulatory Factors (IRFs) play fundamental roles in dendritic cell (DC) differentia-tion and function. In particular, IRFs are critical transducers of TLR signaling and dysregula-tion in this family of factors is associated with the development of autoimmune disorders such as Systemic Lupus Erythematosus (SLE). While several IRFs are expressed in DCs their relative contribution to the aberrant phenotypic and functional characteristics that DCs acquire in autoimmune disease has not been fully delineated. Mice deficient in both DEF6 and SWAP-70 ( = Double-knock-out or DKOmice), two members of a unique family of mole-cules that restrain IRF4 function, spontaneously develop a lupus-like disease. Although autoimmunity in DKOmice is accompanied by dysregulated IRF4 activity in both T and B cells, SWAP-70 is also known to regulate multiple aspects of DC biology leading us to directly evaluate DC development and function in these mice. By monitoring Blimp1 expres-sion and IL-10 competency in DKOmice we demonstrate that DCs in these mice exhibit dysregulated IL-10 production, which is accompanied by aberrant Blimp1 expression in the spleen but not in the peripheral lymph nodes. We furthermore show that DCs from these mice are hyper-responsive to multiple TLR ligands and that IRF4 plays a differential role in in these responses by being required for the TLR4-mediated but not the TLR9-mediated upregulation of IL-10 expression. Thus, DC dysfunction in lupus-prone mice relies on both IRF4-dependent and IRF4-independent pathways