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Receptor Glycosylation Regulates Ly-49 Binding to MHC Class I ¹

Llewellyn H. Mason^2,*, Jami Willette-Brown^*, Stephen K. Anderson, W. Gregory Alvord, Richard L. Klabansky, Howard A. Young^* and John R. Ortaldo^*

^* Laboratory of Experimental Immunology, National Cancer Institute-Clinical Cancer Research, and Basic Research Program, Science Applications International Corporation-Frederick, Frederick, MD 21702; and Data Management Services, National Cancer Institute, Frederick, MD 21702

Murine NK cells express the Ly-49 family of class I MHC-binding receptors that control their ability to lyse tumor or virally infected host target cells. X-ray crystallography studies have identified two predominant contact sites (sites 1 and 2) that are involved in the binding of the inhibitory receptor, Ly-49A, to H-2D^d. Ly-49G2 (inhibitory) and Ly-49D (activating) are highly homologous to Ly-49A and also recognize H-2D^d. However, the binding of Ly-49D and G₂ to H-2D^d is of lower affinity than Ly-49A. All Ly-49s contain N-glycosylation motifs; however, the importance of receptor glycosylation in Ly-49-class I interactions has not been determined. Ly-49D and G₂ contain a glycosylation motif (NTT (221–223)), absent in Ly-49A, adjacent to one of the proposed binding sites for H-2D^d (site 2). The presence of a complex carbohydrate group at this critical site could interfere with class I binding. In this study, we are able to demonstrate for the first time that Ly-49D binds H-2D^d in the presence of mouse ₂-microglobulin. We also demonstrate that glycosylation of the NTT (221–23) motif of Ly-49D inteferes with recognition of H-2D^d. Alteration of the Ly-49D-NTT (221–23) motif to abolish glycosylation at this site resulted in enhanced H-2D^d binding and receptor activation. Furthermore, glycosylation of Ly-49G2 at NTT (221–23) also reduces receptor binding to H-2D^d tetramers. Therefore, the addition of complex carbohydrates to the Ly-49 family of receptors may represent a mechanism by which NK cells regulate affinity for host class I ligands.

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