The Journal of Experimental Medicine
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Published online 8 August 2000.
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© The Rockefeller University Press, 0022-1007/2000/8/447/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 3, August 7, 2000 447-454

Brief Definitive Report

Activating Ly-49D and Inhibitory Ly-49A Natural Killer Cell Receptors Demonstrate Distinct Requirements for Interaction with H2-Dd

Mary C. Nakamuraa, Shigenari Hayashia, Eréne C. Niemia, James C. Ryana, and William E. Seamana,b
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

Correspondence to: Mary C. Nakamura, Immunology Section 111-R, 4150 Clement St., San Francisco, CA 94121. Tel:415-750-2104 Fax:415-750-6920 E-mail: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-Dd. To compare Ly-49D and Ly-49A interactions with H2-Dd, we created mutations in H2-Dd 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-Dd {alpha}1 helix or the {alpha}2 helix abrogated Ly-49D–mediated cytotoxicity, but these changes had no significant effect on Ly-49A–dependent inhibition. Each of three {alpha}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-Dd interactions require distinct determinants compared with Ly-49A/H2-Dd 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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