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Human Invariant NKT Cells Display Alloreactivity Instructed by Invariant TCR-CD1d Interaction and Killer Ig Receptors¹

Scott Patterson^*, Aristeidis Chaidos^*, David C. A. Neville, Alessandro Poggi, Terry D. Butters, Irene A. G. Roberts^* and Anastasios Karadimitris^2,*

^* Department of Hematology, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom; Glycobiology Institute, University of Oxford, Oxford, United Kingdom; and Laboratory of Experimental Oncology D, Department of Translational Oncology, National Institute for Cancer Research (Istituto Scientifica per lo Studio e la Cura dei Tumori), Genoa, Italy

Invariant NKT (iNKT) cells are a subset of highly conserved immunoregulatory T cells that modify a variety of immune responses, including alloreactivity. Central to their function is the interaction of the invariant TCR with glycosphingolipid (GSL) ligands presented by the nonpolymorphic MHC class I molecule CD1d and their ability to secrete rapidly large amounts of immunomodulatory cytokines when activated. Whether iNKT cells, like NK and conventional T cells, can directly display alloreactivity is not known. We show in this study that human iNKT cells and APC can establish a direct cross-talk leading to preferential maturation of allogeneic APC and a considerably higher reactivity of iNKT cells cultured with allogeneic rather that autologous APC. Although the allogeneic activation of iNKT cells is invariant TCR-CD1d interaction-dependent, GSL profiling suggests it does not involve the recognition of disparate CD1d/GSL complexes. Instead, we show that contrary to previous reports, iNKT cells, like NK and T cells, express killer Ig receptors at a frequency similar to that of conventional T cells and that iNKT cell allogeneic activation requires up-regulation and function of activating killer Ig receptors. Thus, iNKT cells can display alloreactivity, for which they use mechanisms characteristic of both NK and conventional T cells.

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 Leukaemia Research Fund, the National Institute for Health Research Biomedical Research Centre Funding Scheme (to S.P. and A.K.), the Glycobiology Institute (to T.D.B. and D.C.A.N.), and Compagnia San Paolo (2007.0265) (to A.P.).

² Address correspondence and reprint requests to Dr. Anastasios Karadimitris, Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, U.K. E-mail address: a.karadimitris{at}imperial.ac.uk

³ Abbreviations used in this paper: iNKT, invariant NKT; aGC, -galactosylceramide; a-GVHD, acute graft-vs-host disease; DC, dendritic cell; GSL, glycosphingolipid; KIR, killer Ig receptor.