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Quantifying the reduction in accessibility of the inhibitory NK cell receptor Ly49A caused by binding MHC class I
Katja E Andersson1, Geoffrey S Williams, Daniel M Davis
1Department of Microbiology, Tumor and Cell Biology and the IRIS Strategic Research Center, Karolinska Institute, Stockholm, Sweden.
Insights
Target cell MHC class I proteins transfer to murine natural killer (NK) cells, reducing Ly49A receptor accessibility. This cis interaction, mediated by H-2D(d) ligands, controls NK cell inhibition.
Area of Science:
- Immunology
- Cellular immunology
- NK cell biology
Background:
- Murine natural killer (NK) cells utilize Ly49 receptors to recognize target cell MHC class I molecules, mediating cellular inhibition.
- Ly49 receptor accessibility to target MHC class I can be modulated by cis interactions within the NK cell membrane.
- MHC class I proteins have been shown to transfer from target cells to NK cells.
Purpose of the Study:
- To investigate the relationship between transferred MHC class I proteins and Ly49 receptor accessibility on NK cells.
- To determine the impact of endogenous ligands, specifically H-2D(d), on Ly49A receptor accessibility.
Main Methods:
- Quantification of transferred MHC class I proteins on NK cells.
- Flow cytometry analysis of Ly49A receptor expression and accessibility.
- Assessment of cis-interactions between Ly49A and H-2D(d) on the NK cell surface.
Main Results:
- The number of transferred MHC class I proteins is directly proportional to the number of Ly49A receptors on the NK cell surface.
- Ly49A+ NK cells from mice expressing the H-2D(d) ligand showed a significant 90% reduction in Ly49A accessibility compared to those from H-2D(d)-negative mice.
- This reduction in accessibility was attributed to both decreased Ly49A expression and cis-interactions between Ly49A and H-2D(d) on the NK cell surface, with approximately 75% of Ly49A receptors occupied in cis.
Conclusions:
- Endogenous H-2D(d) ligands play a critical role in controlling Ly49A receptor accessibility on NK cells.
- Ligand-mediated cis-interactions significantly limit the availability of Ly49A receptors for trans-interactions with target cell MHC class I.
- These findings elucidate a novel mechanism of NK cell regulation involving cis-interactions and MHC class I transfer.
Abstract:
Murine natural killer (NK) cells are inhibited by target cell MHC class I molecules via Ly49 receptors. However, Ly49 receptors can be made inaccessible to target cell MHC class I by a cis interaction with its MHC class I ligand within the NK cell membrane. It has recently been demonstrated that MHC class I proteins transfer from the target cells to the NK cell. Here, we establish that the number of transferred MHC class I proteins is proportional to the number of Ly49A receptors at the NK cell surface. Ly49A+ NK cells from mice expressing the Ly49A ligand H-2D(d) showed a 90% reduction in Ly49A accessibility compared to Ly49A+ NK cells from H-2D(d)-negative mice. The reduction was caused both by lower expression of Ly49A and interactions in cis between Ly49A and H-2D(d) at the NK cell surface. Approximately 75% of the Ly49A receptors on H-2D(d)-expressing NK cells were occupied in cis with endogenous H-2D(d) and only 25% were free to interact with H-2D(d) molecules in trans. Thus, H-2D(d) ligands control Ly49A receptor accessibility through interactions both in cis and in trans.
