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Ig-Like Transcript 4 Inhibits Lipid Antigen Presentation through Direct CD1d Interaction¹

Demin Li^2,*, Lili Wang^*, Li Yu, Eric C. Freundt^*,, Boquan Jin, Gavin R. Screaton and Xiao-Ning Xu^*

^* Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, U.K.; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892; Department of Immunology, the Fourth Military Medical University, Xi’an, China; and Department of Medicine, Imperial College Hammersmith Hospital, Du Cane Road, London, U.K.

NKT cells recognize lipid Ags presented by CD1d molecules and play an important role in the regulation of innate and adaptive immune responses. In this study, we report the identification of a membrane-associated protein, Ig-like transcript 4 (ILT4), as a novel human CD1d receptor that inhibits CD1d-mediated immune responses. We found that native CD1d tetramer generated by mammalian cells was able to specifically bind human monocytes in the peripheral blood, and this binding was at least partly mediated by monocyte-expressed ILT4. The interaction between ILT4 and CD1d involves the two N-terminal domains of ILT4 and the Ag-binding groove of CD1d (1/2 domain). This interaction has been identified on the cell surface as well as in the endosomal and lysosomal compartments. Functional analysis showed that ILT4 could block the loading of lipid Ags such as -GalCer, and consequently inhibited NKT recognition. The interaction between ILT4 and CD1d may provide new insights into the regulation of NKT-mediated immunity.

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 Medical Research Council U.K. and Chinese National Natural Science Foundation (30371346).

² Address correspondence and reprint requests to Dr. Demin Li, MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, United Kingdom. E-mail address: demin.li{at}imm.ox.ac.uk

³ Abbreviations used in this paper: DC, dendritic cell; β₂m, β₂ microglobulin; GalCer, -galactosylceramide; DR5, death receptor 5; ILT4, immunoglobulin-like transcript 4.

⁴ The online version of this article contains supplemental material.