Abstract
The diversity and ligand specificity of activating Ly-49 receptors expressed by murine NK cells are largely unknown. We cloned a new Ly-49-activating receptor, expressed by NK cells of the nonobese diabetic mouse strain, which we have designated Ly-49W. Ly-49W is highly related to the known inhibitory receptor Ly-49G in its carbohydrate recognition domain, exhibiting 97.6% amino acid identity in this region. We demonstrate that the 4D11 and Cwy-3 Abs, thought to be Ly-49G specific, also recognize Ly-49W. Rat RNK-16 cells transfected with Ly-49W mediated reverse Ab-dependent cellular cytotoxicity of FcR-positive target cells, indicating that Ly-49W can activate NK-mediated lysis. We further show that Ly-49W is allo-MHC specific: Ly-49W transfectants of RNK-16 only lysed Con A blasts expressing H-2(k) or H-2(d) haplotypes, and Ab-blocking experiments indicated that H-2D(k) and D(d) are ligands for Ly-49W. Ly-49W is the first activating Ly-49 receptor demonstrated to recognize an H-2(k) class I product. Ly-49G and Ly-49W represent a new pair of NK receptors with very similar ligand-binding domains, but opposite signaling functions.
Highlights
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Investigation of Ly-49 expression in mouse strains such as 129J and CBA/J have resulted in the identification of novel activating Ly-49 molecules (40, 42)
We examine Ly-49 expression in the nonobese diabetic (NOD) mouse strain, an animal model of insulin-dependent diabetes mellitis
Summary
KIR, killer Ig-related receptor; ADCC, Ab-dependent cellular cytotoxicity; CRD, carbohydrate recognition domain; ITIM, immunoreceptor tyrosine-based inhibitory motif; NOD, nonobese diabetic; NOR, nonobese diabetes-resistant; PA, protein A; PG, protein G; rADCC, reverse ADCC. Engagement of the inhibitory receptor with its class I ligand on the target cell results in tyrosine phosphorylation of the ITIM (13, 14). All NK cell-inhibitory receptor families contain members that lack ITIM sequences. For the KIR and Ly-49 families, this adaptor is the DAP12 signaling molecule that contains an immunoreceptor tyrosine-based activation motif (11, 15–17). Ly-49D and Ly-49P recognize the H-2Dd class I MHC molecule, similar to the ITIM-containing inhibitory receptors, Ly-49A and Ly-49G (21–25). I MHC molecules with strong and moderate reactivity toward H-2Dk and H-2Dd, respectively This is the first report of an activating Ly-49 molecule recognizing an H-2k product and provides further support for the possibility that activating Ly-49 receptors recognize class I MHC ligands
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