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Novel KIR3DL1 Alleles and Their Expression Levels on NK Cells: Convergent Evolution of KIR3DL1 Phenotype Variation?^1,2

Rasmi Thomas^3,*, Eriko Yamada^3,, Galit Alter, Maureen P. Martin^*, Arman A. Bashirova, Paul J. Norman^¶, Marcus Altfeld, Peter Parham^¶, Stephen K. Anderson^*, Daniel W. McVicar and Mary Carrington^4,*

^* Cancer and Inflammation Program, Laboratory of Experimental Immunology, Science Applications International-Frederick and Cancer and Inflammation Program, Laboratory of Experimental Immunology, National Cancer Institute, Frederick, MD 21702; Partners AIDS Research Center, Infectious Disease Unit, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, MA 02129; Johns Hopkins University School of Medicine, Baltimore, MD 21231; and ^¶ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305

KIR3DL1 shows extensive polymorphism, and its variation has functional significance in terms of cell-surface expression levels and inhibitory capacity. We characterized nine KIR3DL1 alleles (*022, *028, *029, *033, *035, *051, *052, *053, and *054), four of which were identified for the first time in this study, and compared them to known alleles in phylogenetic analysis. Blood was available from eight individuals with these alleles, and cell-surface expression on NK cells could be determined for six of them using the KIR3DL1-specific Ab DX9. Four of the alleles were expressed at clearly detectable levels, and two others showed exceptionally low levels of expression. Site-directed mutagenesis demonstrated that single amino acid changes can result in either diminished or enhanced DX9 staining compared with the respective related KIR3DL1 allotypes. These results raise the possibility that KIR3DL1 evolution maintains variation in KIR3DL1 cell-surface expression levels, potentially due to the effect of such variation on functional capacity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-C0-12400. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. A.B. was supported by National Institutes of Health Grant DA13324.

² The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

³ R.T. and E.Y. contributed equally to this work.

⁴ Address correspondence and reprint requests to Dr. Mary Carrington, Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702. E-mail address: carringt{at}ncifcrf.gov

⁵ Abbreviations used in this paper: KIR, killer cell Ig-like receptor; MFI, mean fluorescence intensity.