Initiation and Limitation of Ly-49A NK Cell Receptor Acquisition by T Cell Factor-1

• Published in: The Journal of immunology (1950) 2003-07, Vol.171 (2), p.769-775
• Main Authors: Ioannidis, Vassilios, Kunz, Beatrice, Tanamachi, Dawn M, Scarpellino, Leonardo, Held, Werner
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Antigens, Ly - biosynthesis; Antigens, Ly - genetics; Antigens, Ly - metabolism; beta Catenin; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Cytoskeletal Proteins - physiology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Dose-Response Relationship, Immunologic; Gene Expression Regulation - immunology; Gene Rearrangement - immunology; Hepatocyte Nuclear Factor 1-alpha; Humans; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lectins, C-Type; Lymphoid Enhancer-Binding Factor 1; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Promoter Regions, Genetic - immunology; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Isoforms - physiology; Receptors, Immunologic - metabolism; Receptors, NK Cell Lectin-Like; T Cell Transcription Factor 1; Trans-Activators - genetics; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; Transfection
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.2.769

The establishment of clonally variable expression of MHC class I-specific receptors by NK cells is not well understood. The Ly-49A receptor is used by approximately 20% of NK cells, whereby most cells express either the maternal or paternal allele and few express simultaneously both alleles. We have previously shown that NK cells expressing Ly-49A were reduced or almost absent in mice harboring a single or no functional allele of the transcription factor T cell factor-1 (TCF-1), respectively. In this study, we show that enforced expression of TCF-1 in transgenic mice yields an expanded Ly-49A subset. Even though the frequencies of Ly-49A(+) NK cells varied as a function of the TCF-1 dosage, the relative abundance of mono- and biallelic Ly-49A cells was maintained. Mono- and biallelic Ly-49A NK cells were also observed in mice expressing exclusively a transgenic TCF-1, i.e., expressing a fixed amount of TCF-1 in all NK cells. These findings suggest that Ly-49A acquisition is a stochastic event due to limiting TCF-1 availability, rather than the consequence of clonally variable expression of the endogenous TCF-1 locus. Efficient Ly-49A acquisition depended on the expression of a TCF-1 isoform, which included a domain known to associate with the TCF-1 coactivator beta-catenin. Indeed, the proximal Ly-49A promoter was beta-catenin responsive in reporter gene assays. We thus propose that Ly-49A receptor expression is induced from a single allele in occasional NK cells due to a limitation in the amount of a transcription factor complex requiring TCF-1.