Severe defect in thymic development in an insertional mutant mouse model.
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.
Assarsson
Erika
E
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. erika@liai.org
Chambers
Benedict J
BJ
Högstrand
Kari
K
Berntman
Emma
E
Lundmark
Carin
C
Fedorova
Ludmila
L
Imreh
Stefan
S
Grandien
Alf
A
Cardell
Susanna
S
Rozell
Björn
B
Ljunggren
Hans-Gustaf
HG
D000818:Animals; D000950:Antigens, Ly; D000954:Antigens, Surface / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology; D053533:Keratin-8 / Q000032:analysis; D037181:Lectins, C-Type / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D055651:NK Cell Lectin-Like Receptor Subfamily B; D051761:Paired Box Transcription Factors / Q000032:analysis; D010641:Phenotype; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D013950:Thymus Gland / Q000002:abnormalities* / Q000473:pathology
D000950:Antigens, Ly; D000954:Antigens, Surface; C527203:KLRB1 protein, human; D053533:Keratin-8; C527211:Klrb1c protein, mouse; C486595:Krt8 protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D051761:Paired Box Transcription Factors; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; C070835:PAX1 transcription factor