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The Journal of Immunology, 2005, 175: 7303-7310.
Copyright © 2005 by The American Association of Immunologists

Targeted Expression of Human CD1d in Transgenic Mice Reveals Independent Roles for Thymocytes and Thymic APCs in Positive and Negative Selection of V{alpha}14i NKT Cells1

Jens Schümann2,*, Paola Pittoni2,{dagger}, Elena Tonti{dagger}, H. Robson MacDonald*, Paolo Dellabona3,{dagger} and Giulia Casorati3,{dagger}

* Ludwig Institute for Cancer Research, Epalinges, Switzerland; and {dagger} Experimental Immunology Unit, Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, Dipartimento di Biotecnologie, H. San Raffaele Scientific Institute, Milan, Italy

CD1d-dependent invariant V{alpha}14 (V{alpha}14i) NKT cells are innate T lymphocytes expressing a conserved semi-invariant TCR, consisting, in mice, of the invariant V{alpha}14-J{alpha}18 TCR {alpha}-chain paired mostly with V{beta}8.2 and V{beta}7. The cellular requirements for thymic positive and negative selection of V{alpha}14i NKT cells are only partially understood. Therefore, we generated transgenic mice expressing human CD1d (hCD1d) either on thymocytes, mainly CD4+ CD8+ double positive, or on APCs, the cells implicated in the selection of V{alpha}14i NKT cells. In the absence of the endogenous mouse CD1d (mCD1d), the expression of hCD1d on thymocytes, but not on APCs, was sufficient to select V{alpha}14i NKT cells that proved functional when activated ex vivo with the Ag {alpha}-galactosyl ceramide. V{alpha}14i NKT cells selected by hCD1d on thymocytes, however, attained lower numbers than in control mice and expressed essentially V{beta}8.2. The low number of V{beta}8.2+ V{alpha}14i NKT cells selected by hCD1d on thymocytes was not reversed by the concomitant expression of mCD1d, which, instead, restored the development of V{beta}7+ V{alpha}14i NKT cells. V{beta}8.2+, but not V{beta}7+, NKT cell development was impaired in mice expressing both hCD1d on APCs and mCD1d. Taken together, our data reveal that selective CD1d expression by thymocytes is sufficient for positive selection of functional V{alpha}14i NKT cells and that both thymocytes and APCs may independently mediate negative selection.




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