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Peripheral NK1.1^– NKT Cells Are Mature and Functionally Distinct from Their Thymic Counterparts¹

Finlay W. McNab^*, Daniel G. Pellicci^*, Kenneth Field^*, Gurdyal Besra, Mark J. Smyth, Dale I. Godfrey^2,* and Stuart P. Berzins^2,3,*

^* Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia; School of Biosciences, University of Birmingham, Edgbaston, United Kingdom; and Cancer Immunology Program, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria, Australia

One interesting aspect of NKT cell development is that although they are thymus dependent, the pivotal transition from NK1.1^– to NK1.1⁺ can often take place after immature NK1.1^– NKT cells are exported to the periphery. NK1.1^– NKT cells in general are regarded as immature precursors of NK1.1⁺ NKT cells, meaning that peripheral NK1.1^– NKT cells are regarded as a transient, semimature population of recent thymic emigrant NKT cells. In this study, we report the unexpected finding that most NK1.1^– NKT cells in the periphery of naive mice are actually part of a stable, mature and functionally distinct NKT cell population. Using adult thymectomy, we show that the size of the peripheral NK1.1^– NKT cell pool is maintained independently of thymic export and is not the result of NK1.1 down-regulation by mature cells. We also demonstrate that most peripheral NK1.1^– NKT cells are functionally distinct from their immature thymic counterparts, and from NK1.1⁺ NKT cells in the periphery. We conclude that the vast majority of peripheral NK1.1^– NKT cells are part of a previously unrecognized, mature NKT cell subset.

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 National Health and Medical Research Council of Australia (NHMRC) Program Grant 251608 and 454569. The authors also acknowledge the following support: F.W.M., National Health and Medical Research Council of Australia Dora Lush postgraduate fellowship; D.G.P., D.I.G., and M.J.S., National Institutes of Health, National Cancer Institute RO1 Grant 106377-04; D.I.G. and M.J.S., National Health and Medical Research Council of Australia research fellowships; S.P.B., National Health and Medical Research Council of Australia career development award and a National Health and Medical Research Council of Australia Project Grant 454363; G.S.B., a Personal Research Chair from Mr. James Bardrick, a Royal Society Wolfson Research Merit Award as a former Lister Institute-Jenner Research Fellow, the Medical Research Council (G9901077 and G0500590), and The Wellcome Trust (081569/2/06/2).

² D.I.G. and S.P.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Stuart Berzins, University of Melbourne, Royal Parade, Parkville, Victoria, Australia. E-mail address: berzins{at}unimelb.edu.au

⁴ Abbreviations used in this paper: RTE, recent thymic emigrant; FCS.PBS, PBS containing 2% FCS; RPMI-FTOC, RPMI 1640 supplemented with 10% v/v FCS, 2 mM glutamax, 10 mM HEPES, 0.5 mg/ml folic acid, and 0.2 mg/ml glucose; FTOC, fetal thymic organ cultures; NKR, NK cell receptors.

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