Orientation-dependent CD45 inhibition with viral and engineered ligands 2152

Abstract Description CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of three immunoglobulin domains assembled as”beads on a string” that compel CD45 into a closely abutted dimer by cross-linking the CD45 D3 domain, leading to steric inhibition of its intracellular phosphatase activity. Inspired by the E3/49K mechanism, we engineered CD45 surrogate ligands that can fine-tune T cell activation by dimerizing CD45 into different orientations and proximities. The adenovirus E3/49K protein has taught us that, despite a lack of a known ligand, CD45 activity can be modulated by extracellular dimerizing ligands that perturb its phosphatase activity and alter T cell responses. Funding Sources This work was supported by NCI R01 CA177684 (K.C.G.); Howard Hughes Medical Institute (K.C.G.); Ludwig Institute for Cancer Research (K.C.G.); NCI, R37 CA239072 (E.H.); NIH, DP2 CA272092(R.G.M.); and CRI Lloyd J. Old STAR, CRI4960 (R.G.M.). Topic Categories Viral Immunology (VIR)