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The human adaptive immune system serves as the primary defense against pathogens. While the human adaptive immune response is powered by many components, the Major Histocompatibility Class II (MHCII) molecules lie at the heart of the machinery of the immune system. MHCII display of antigens triggers a cascade of events leading to the immune response. Lack of MHCII expression causes severe immunodeficiency disorders, whereas overproduction of these molecules can cause a variety of autoimmune diseases. The production of MHCII molecules is regulated by a multi-protein complex that includes the Regulatory Factor X (RFX) protein complex, which is comprised of three subunits, RFX5, RFXAP, and RFXB. Mutations or deletions in any RFX subunit that prevents the formation of the MHCII enhanceosome abolishes MHCII expression. A better understanding of how the RFX complex assembles will provide insight into the rational design of novel immunosuppressive therapeutic agents. Our structural analysis of the RFX complex elucidates this complex formation, in efforts to move towards this therapeutic goal.