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Two Novel NKG2D Ligands of the Mouse H60 Family with Differential Expression Patterns and Binding Affinities to NKG2D¹

Akio Takada^2,*,, Shigeru Yoshida^2,*,, Mizuho Kajikawa, Yukiko Miyatake^*, Utano Tomaru^*, Masaharu Sakai, Hitoshi Chiba, Katsumi Maenaka, Daisuke Kohda, Kazunori Fugo^* and Masanori Kasahara^3,*

^* Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Pathology, Sapporo City General Hospital, Sapporo, Japan; Department of Health Sciences, Hokkaido University School of Medicine, Sapporo, Japan; and Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

H60, originally described as a dominant minor histocompatibility Ag, is an MHC class I-like molecule that serves as a ligand for the NKG2D receptor. In the present study, we identified two novel mouse chromosome 10-encoded NKG2D ligands structurally resembling H60. These ligands, which we named H60b and H60c, encode MHC class I-like molecules with two extracellular domains. Whereas H60b has a transmembrane region, H60c is a GPI-anchored protein. Recombinant soluble H60b and H60c proteins bound to NKG2D with affinities typical of cell–cell recognition receptors (K_d = 310 nM for H60b and K_d = 8.7 µM for H60c). Furthermore, expression of H60b or H60c rendered Ba/F3 cells susceptible to lysis by NK cells, thereby establishing H60b and H60c as functional ligands for NKG2D. H60b and H60c transcripts were detected only at low levels in tissues of healthy adult mice. Whereas H60b transcripts were detectable in various tissues, H60c transcripts were detected mainly in the skin. Infection of mouse embryonic fibroblasts with murine cytomegalovirus induced expression of H60b, but not H60c or the previously known H60 gene, indicating that transcriptional activation of the three types of H60 genes is differentially regulated. The present study adds two new members to the current list of NKG2D ligands.

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-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by grants from the Japan Science and Technology Agency, the Northtec Foundation, the Takeda Science Foundation, and the Yasuda Medical Foundation.

² These authors contributed equally to this work. The order of the first two authors is arbitrary.

³ Address correspondence and reprint requests to Dr. Masanori Kasahara, Department of Pathology, Hokkaido University Graduate School of Medicine, North-15, West-7, Sapporo 060-8638, Japan. E-mail: mkasaha{at}med.hokudai.ac.jp

⁴ Abbreviations used in this paper: MICA, MICB, MHC class I-related chains A and B; EST, expressed sequence tag; GSP, gene-specific primer; MCMV, murine CMV; MEF, mouse embryonic fibroblast; PI-PLC, phosphatidylinositol-specific phospholipase C; RAE1, retinoic acid early inducible-1; RAET, retinoic acid early transcript; SPR, surface plasmon resonance; ULBP, UL16-binding protein; UT, untranslated.