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MHC Class I Recognition by NK Receptors in the Ly49 Family Is Strongly Influenced by the ₂-Microglobulin Subunit¹

Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden

NK cell recognition of targets is strongly affected by MHC class I specific receptors. The recently published structure of the inhibitory receptor Ly49A in complex with H-2D^d revealed two distinct sites of interaction in the crystal. One of these involves the ₁, ₂, ₃, and ₂-microglobulin (₂m) domains of the MHC class I complex. The data from the structure, together with discrepancies in earlier studies using MHC class I tetramers, prompted us to study the role of the ₂m subunit in MHC class I-Ly49 interactions. Here we provide, to our knowledge, the first direct evidence that residues in the ₂m subunit affect binding of MHC class I molecules to Ly49 receptors. A change from murine ₂m to human ₂m in three different MHC class I molecules, H-2D^b, H-2K^b, and H-2D^d, resulted in a loss of binding to the receptors Ly49A and Ly49C. Analysis of the amino acids involved in the binding of Ly49A to H-2D^d in the published crystal structure, and differing between the mouse and the human ₂m, suggests the cluster formed by residues Lys³, Thr⁴, Thr²⁸, and Gln²⁹, as a potentially important domain for the Ly49A-H-2D^d interaction. Another possibility is that the change of ₂m indirectly affects the conformation of distal parts of the MHC class I molecule, including the ₁ and ₂ domains of the heavy chain.

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