The Journal of Experimental Medicine
IN Cell Analyzer 2000
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© The Rockefeller University Press, 0022-1007/1999/4/1265/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 8, April 19, 1999 1265-1274

Articles

The Transmembrane Sequence of Human Histocompatibility Leukocyte Antigen (HLA)-C as a Determinant in Inhibition of a Subset of Natural Killer Cells

Daniel M. Davis, Ofer Mandelboim, Isabel Luque, Eishi Baba, Jonathan Boyson, and Jack L. Strominger

From the Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138

Molecular interactions with the extracellular domains of class I major histocompatibility complex proteins are major determinants of immune recognition that have been extensively studied both physically and biochemically. However, no immunological function has yet been placed on the transmembrane or cytoplasmic amino acid sequences of these proteins despite strict conservation of unique features within each class I major histocompatibility complex locus. Here we report that lysis by a subset of natural killer (NK) cells inhibited by target cell expression of human histocompatibility leukocyte antigen (HLA)-Cw6 or -Cw7 was not inhibited by expression of chimeric proteins consisting of the extracellular domains of HLA-C and the COOH-terminal portion of HLA-G. Assays using transfectants expressing a variety of HLA-Cw6 mutants identified the transmembrane sequence and, in particular, cysteine at position 309 as necessary for inhibition of 68% (25/37) of NK cell lines and 23% (33/145) of NK clones tested. Moreover, these NK clones inhibited by target cell expression of HLA-Cw6 and dependent upon the transmembrane sequence were found not to express or to only dimly express NK inhibitory receptors (NKIR1) that are EB6/HP3E4-positive. Furthermore, assays using monoclonal antibody blocking suggest that an NK receptor other than NKIR1 or CD94 is responsible for recognition dependent upon the transmembrane sequence of HLA-Cw6.

Key Words: NK cells • class I MHC protein • transmembrane sequence • NK receptors • cysteine

Address correspondence to Jack L. Strominger, Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Ave., Cambridge, MA 02138. Phone: 617-495-2733; Fax: 617-496-8351; E-mail: jlstrom{at}fas.harvard.edu

Presented in abstract form at The British Society for Immunology 6th Annual Congress, Harrogate, England. 1–4 December 1998.

Abbreviations used: β2m, β2-microglobulin; GPI, glycosylphosphatidylinositol; NKIR, natural killer cell inhibitory receptor.


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