Abstract
Size-dependent protein segregation at the cell–cell contact interface has been suggested to be critical for regulation of lymphocyte function. We investigated the role of ligand dimensions in regulation of mouse NK-cell activation and inhibition. Elongated forms of H60a, a mouse NKG2D ligand, were generated and expressed stably in the RMA cell line. RMA cells expressing the normal size H60a were lysed efficiently by both freshly isolated and IL-2 stimulated C57BL/6 mouse-derived NK cells; however the level of lysis decreased as the H60a ligand size increased. Importantly, H60a elongation did not affect NKG2D binding, as determined by soluble NKG2D tetramer staining, and by examining NK-cell target cell conjugate formation. CHO cells are efficient at activating NK cells from C57BL/6 mice, and expression of a single chain form of H-2Kb, a ligand for the mouse inhibitory receptor Ly49C, strongly inhibited such activation of Ly49C/I positive NK cells. Elongation of H-2Kb resulted in decreased inhibition of both lysis and IFN-γ production by NK cells. These results establish that small ligand dimensions are important for both NK-cell activation and inhibition, and suggest that there are shared features between the mechanisms of receptor triggering on different types of lymphocytes.
Highlights
Receptor–ligand interactions are of fundamental importance in the regulation of lymphocyte function
In order to investigate the importance of ligand dimensions in NK-cell activation, we generated elongated forms of H60a, a NKG2D ligand that is a structural homologue of the a1a2 platform of MHC class I
We have demonstrated the importance of small ligand dimensions for CD81 T-cell activation by experimental elongation of MHC class I molecules [2, 3]
Summary
Receptor–ligand interactions are of fundamental importance in the regulation of lymphocyte function. Extensive information is available on structural features of lymphocyte receptors, and the signalling pathways they initiate. The mechanisms of lymphocyte receptor triggering, defined as the sequence of molecular events that link receptor ligation to initiation of the signalling pathways, remain much less well characterized The importance of ligand dimensions for CD81 T-cell activation has been demonstrated by experimental elongation of MHC class I molecules, which resulted in a marked reduction of TCRdependent signalling and T-cell effector function [2, 3]. The significance of size-dependent segregation of proteins during lymphocyte interactions has been shown by elongation of CD48, a ligand for the T-cell co-receptor CD2 [5, 6], and by experimental reduction in size of
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