Initiation and limitation of Ly-49A NK cell receptor acquisition by T cell factor-1.
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.
Ioannidis
Vassilios
V
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
Kunz
Béatrice
B
Tanamachi
Dawn M
DM
Scarpellino
Léonardo
L
Held
Werner
W
D000483:Alleles; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation / Q000276:immunology; D015321:Gene Rearrangement / Q000276:immunology; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism*; D055630:Receptors, NK Cell Lectin-Like; D051822:T Cell Transcription Factor 1; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D051176:beta Catenin
D000950:Antigens, Ly; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D037181:Lectins, C-Type; D051821:Lymphoid Enhancer-Binding Factor 1; D020033:Protein Isoforms; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin