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* Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, San Diego, CA 92122;
Department of Cell and Molecular Biology, Lund University, Lund, Sweden;
Divisions of Clinical Research Center and Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;
¶ Department of Microbiology, Tumor Biology and Cell Biology, Karolinska Institutet, Stockholm, Sweden; and
|| Department of Medical Microbiology and Immunology, Göteborg University, Göteborg, Sweden
Transgenic mice were generated expressing NK1.1, an NK cell-associated receptor, under control of the human CD2 promoter. Unexpectedly, one of the founder lines, Tg66, showed a marked defect in thymic development characterized by disorganized architecture and small size. Mapping of the transgene insertion by fluorescence in situ hybridization revealed integration in chromosome 2, band G. Already from postnatal day 3, the thymic architecture was disturbed with a preferential loss of cortical thymic epithelial cells, a feature that became more pronounced over time. Compared with wild-type mice, total thymic cell numbers decreased dramatically between 10 and 20 days of age. Thymocytes isolated from adult Tg66 mice were predominantly immature double-negative cells, indicating a block in thymic development at an early stage of differentiation. Consequently, Tg66 mice had reduced numbers of peripheral CD4+ and CD8+ T cells. Bone marrow from Tg66 mice readily reconstituted thymi of irradiated wild-type as well as RAG-deficient mice. This indicates that the primary defect in Tg66 mice resided in nonhemopoietic stromal cells of the thymus. The phenotype is observed in mice heterozygous for the insertion and does not resemble any known mutations affecting thymic development. Preliminary studies in mice homozygous for transgene insertion reveal a more accelerated and pronounced phenotype suggesting a semidominant effect. The Tg66 mice may serve as a useful model to identify genes regulating thymic epithelial cell differentiation, thymic development, and function.
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1 This work was supported by the David and Astrid Hagelén Foundation (to E.A.), the Swedish Foundation for Strategic Research, the Karolinska Institutet, the Swedish Society for Medical Research, the Swedish Research Council, the Lars Hierta’s Foundation, the Wenner-Gren Foundations (to E.A.), the Swedish Cancer Society, and Wallenberg Consortium North.
2 Address correspondence and reprint requests to Dr. Erika Assarsson, Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: erika{at}liai.org
3 E.A. and B.J.C. contributed equally.
4 Abbreviations used in this paper: TEC, thymic epithelial cell; tg, transgenic; CMJ, corticomedullary junction; FISH, fluorescence in situ hybridization; Chr, chromosome; CK, cytokeratin; dpc, days postcoitum; DAPI, 4',6'-diamidino-2-phenylindole; MFI, mean fluorescence intensity; DP, double positive; SP, single positive; TN, triple negative; LN, lymph node; tg, transgenic; wt, wild type.
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