Sequence, structure and immune functions: Structural basis for T cell regulation by SLAM, CD28/B7 and TIM family receptors
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Regulation of T cell activation is critical for both eliminating invading pathogens and maintaining self-tolerance. A number of distinct families of co-stimulatory molecules, including the SLAM family, the CD28/B7 family and the TIM family receptors, have been found to modulate the strength, duration and course of T cell responses. By utilizing a structural based approach, we investigated the structural features of ligand-receptor recognition underlying the biological function within SLAM family, CD28/B7 family and TIM family.;The signaling lymphocyte activation molecule (SLAM) family includes homophilic and heterophilic receptors that modulate both adaptive and innate immune responses. NTB-A, CD84 and Ly-9 are homophilic receptors in SLAM family that modulate T cell functions. Our crystal structures of the NTB-A, CD84 and Ly-9 revealed an overall similar orthogonal, beta-sheet to beta-sheet, symmetric homophilic interaction. Differences in the homophilic interfaces would be expected to prevent the formation of undesired heterodimers among the SLAM family homophilic receptors. Programmed death-1 (PD-1) is a unique member of the CD28/B7 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. Our high resolution crystal structure of the complex formed between the complete ectodomains of murine PD-1 and PD-L2 revealed a 1:1 receptor:ligand stoichiometry and displayed a binding interface and overall molecular organization distinct from that observed in the CTLA-4/B7 complexes, another inhibitory co-stimulatory receptor/ligand pair. TIM-3, a member of the T cell immunoglobulin mucin (TIM) family of receptors, negatively regulates Th1-mediated immunity and promotes peripheral tolerance. Here we reported that TIM-3 can specifically bind to both phosphatidylserine (PS) and carbohydrate with different affinities. Our crystal structures of TIM-3 in complex with PS demonstrated that the unique cleft structure present in TIM-3 Ig domain is required for the PS binding. Furthermore, our crystal structures of TIM-3 in complex with monosaccharide suggested TIM-3 also utilizes the same ligand binding pocket to bind the second ligand, carbohydrate. The crystal structures of TIM receptor-ligand complexes provide models for receptor-ligand interactions in the TIM family. The structural features of these major co-stimulatory family receptors underlie the receptor-ligand recognition, affinity, specificity and the oligomeric state, all of which directly impact the downstream signaling transduction and regulate immune responses.