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Brief Definitive Report

^a Department of Medicine, University of California, San Francisco, California 94143 and Veterans Affairs Medical Center, San Francisco, California 94121
^b Department of Microbiology and Immunology, University of California, San Francisco, California 94143
Immunology Section 111-R, 4150 Clement St., San Francisco, CA 94121.415-750-6920415-750-2104

marynak{at}itsa.ucsf.edu

The activating Ly-49D receptor and the inhibitory Ly-49A receptor mediate opposing effects on natural killer (NK) cell cytotoxicity after interaction with the same major histocompatibility complex ligand, H2-D^d. To compare Ly-49D and Ly-49A interactions with H2-D^d, we created mutations in H2-D^d and examined the functional ability of these mutants to activate lysis through Ly-49D or to inhibit lysis through Ly-49A. Specific single amino acid changes in either the H2-D^d ₁ helix or the ₂ helix abrogated Ly-49D–mediated cytotoxicity, but these changes had no significant effect on Ly-49A–dependent inhibition. Each of three ₂ domain mutations in the floor of the peptide binding groove reduced functional recognition by either Ly-49D or Ly-49A, but all three were required to fully abrogate inhibition by Ly-49A. Our studies indicate that Ly-49D/H2-D^d interactions require distinct determinants compared with Ly-49A/H2-D^d interactions. These differences have important implications for the integration of activating and inhibitory signals in NK cells.

Key Words: natural killer cells • major histocompatibility complex • receptors • cytotoxicity • rodent

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