Transmembrane Interactions as Immunotherapeutic Targets: Lessons from Viral Pathogenesis

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Multichain immune recognition receptors (MIRRs) represent a family of structurally related but functionally different surface receptors expressed on different cells of the immune system. A distinctive and common structural characteristic of MIRR family members is that the extracellular recognition domains and intracellular signaling domains are located on separate subunits. How extracellular ligand binding triggers MIRRs and initiates intracellular signal transduction processes is not clear. A novel model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, suggests possible molecular mechanisms and reveals the MIRR transmembrane interactions as universal therapeutic targets for a variety of MIRR-mediated immune disorders. Intriguingly, these interactions have been recently shown to play an important role in human immunodeficiency virus and cytomegalovirus pathogenesis. In this chapter, I demonstrate how the SCHOOL model, together with the lessons learned from viral pathogenesis, can be used practically for rational drug design and the development of new therapeutic approaches to treat a variety of seemingly unrelated disorders, such as T cell-mediated skin diseases and platelet disorders.