| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,¶
* Department of Human Genetics, McGill University, Montreal, Quebec, Canada;
McGill Centre for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada;
Department of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143;
Istituto Giannina Gaslini, Medicina Molecolare, Genoa, Italy; and
¶ Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
NK cell function is regulated by Ly49 receptors in mice and killer cell Ig-like receptors in humans. Although inhibitory Ly49 and killer cell Ig-like receptors predominantly ligate classical MHC class I molecules, recent studies suggest that their activating counterparts recognize infection. The quintessential example is resistance to the mouse CMV in C57BL/6 mice, which depends on the functional recognition of m157, a mouse CMV-encoded MHC class I-like molecule, by Ly49H, an activating NK cell receptor. We have taken advantage of the natural variation in closely related members of the Ly49C-like receptors and the availability of Ly49 crystal structures to understand the molecular determinants of the Ly49H-m157 interaction and to identify amino acid residues discriminating between m157 binding and nonbinding receptors. Using a site-directed mutagenesis approach, we have targeted residues conserved in receptors binding to m157 (Ly49H and Ly49I129) but different from receptors lacking m157 recognition (Ly49C, Ly49IB6, and Ly49U). Wild-type and mutant receptors were transfected into reporter cells, and physical binding as well as functional activation by m157 was studied. Our findings suggested that the Ly49 MHC class I contact "site 2," I226, may not be involved in m157 binding. In contrast, residue Y146 and G151, mapping at the receptor homodimer interface, are likely critical for functional recognition of the m157 glycoprotein. Our combined functional and three-dimensional modeling approach suggested that the architecture of the Ly49H dimer is crucial to accessing m157, but not MHC class I. These results link Ly49 homodimerization variability to the direct recognition of pathogen products.
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 by grants from the Canadian Institutes of Health Research and the Canadian Genetic Diseases Network. A.K. is a Canadian Institutes of Health Research Training Fellow in Infectious Diseases and Autoimmunity and is also supported by a McGill Majors Fellowship. L.L.L. is an American Cancer Society Research Professor and is funded by National Institutes of Health Grant AI068129.
2 Address correspondence and reprint requests to Dr. Silvia M. Vidal, McGill Duff Medical Building, 3775 University Street, Room 613, Montreal, H3A 2B4 Quebec, Canada. E-mail address: silvia.vidal{at}mcgill.ca
3 Abbreviations used in this paper: KIR, killer cell Ig-like receptor; CTLD, C-type lectin-like domain; MCMV, mouse CMV.
This article has been cited by other articles:
|
|
 |
|
  A. H. Davis, N. V. Guseva, B. L. Ball, and J. W. Heusel Characterization of Murine Cytomegalovirus m157 from Infected Cells and Identification of Critical Residues Mediating Recognition by the NK Cell Receptor Ly49H J. Immunol., July 1, 2008; 181(1): 265 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K. Kaiser, J. C. Pizarro, J. Kerns, and R. K. Strong Structural basis for NKG2A/CD94 recognition of HLA-E PNAS, May 6, 2008; 105(18): 6696 - 6701. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
