Cis interactions of immunoreceptors with MHC and non-MHC ligands

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Abstract
Cell-surface receptors interact with ligands expressed by other cells to allow cell-to-cell communication (trans interactions). In addition, a small number of cell-surface receptors can engage the equivalent ligand expressed by the same cell (cis interaction). Immunoreceptors that can bind MHC class I ligand in cis and in trans belong to two structurally distinct receptor families — that is, the C-type lectin-like Ly49 receptors and the immunoglobulin-like receptors LILRB1 (leukocyte immunoglobulin-like receptor B1) and PIRB (paired immunoglobulin-like receptor B). In addition, immunoglobulin-like Siglecs bind sialic-acid-modified glycoproteins in cis. Structural considerations suggest that ligand binding in cis versus trans depends on unusually long stalk regions (Ly49 receptors) or on very flexible (or multiple) interdomain hinges (LILRB1 and PIRB). Cis interactions are a feature of immunoreceptors that inhibit rather than activate cellular functions. Cis interactions can increase or decrease the threshold at which cellular activation signalling translates into a biological response. It facilitates the activation of natural killer (NK) cells, as the number of inhibitory Ly49 receptors available to functionally interact with the MHC class I ligand in trans is reduced. By contrast, the PIRB–MHC class I interaction dampens mast-cell activation.