| Summary: | We have recently shown that certain anti-MHC-I mAbs in human and murine systems can stimulate immune responses to tumors and infections by competitively blocking inhibitory signals delivered by MHC-I-specific inhibitory receptors of several inflammatory cell types [1,2]. To understand such functions, we determined the structure of a broadly reactive anti-human MHC-I mAb, B1.23.2, in complex with the MHC-I molecule HLA- B*44:05 by both X-ray crystallography and cryo-electron microscopy (cryo-EM). Structural models determined by the two methods were identical and revealed that B1.23.2 binds a highly conserved site on the a2-1 helix. Structural comparison to killer immunoglobulin receptors (KIR)/MHC-I (HLA) complexes reveals a mechanism by which B1.23.2 blocks inhibitory KIR interactions, leading to natural killer (NK) cell activation (Figure.1). The function of such anti-MHC-I mAbs to block the interactions with NK inhibitory receptors is distinct from most available mAbs that bind the NK cell receptor directly. Applying such anti-MHC-I mAbs to suppress tumor growth may offer new avenues for immunotherapeutic intervention against cancer.
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