Article: article from journal or magazin.
Positive and negative roles of the trans-acting T cell factor-1 for the acquisition of distinct Ly-49 MHC class I receptors by NK cells.
Journal of immunology
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Members of the Ly-49 gene family code for class I MHC-specific receptors that regulate NK cell function. Due to a combinatorial distribution of Ly-49 receptors, NK cells display considerable clonal heterogeneity. The acquisition of one Ly-49 receptor, Ly-49A is strictly dependent on the transcriptional trans-acting factor T cell-specific factor-1 (TCF-1). Indeed, TCF-1 binds to two sites in the Ly-49a promoter and regulates its activity, suggesting that the Ly-49a gene is a direct TCF-1 target. TCF-1 deficiency resulted in the altered usage of additional Ly-49 receptors. We show in this study, using TCF-1 beta(2)-microglobulin double-deficient mice, that these repertoire alterations are not due to Ly-49/MHC class I interactions. Our findings rather suggest a TCF-1-dependent, cell autonomous effect on the acquisition of multiple Ly-49 receptors. Besides reduced receptor usage (Ly-49A and D), we also observed no effect (Ly-49C) and significantly expanded (Ly-49G and I) receptor usage in the absence of TCF-1. These effects did not in all cases correlate with the presence of TCF binding sites in the respective proximal promoter. Therefore, besides TCF-1 binding to the proximal promoter, Ly-49 acquisition may also be regulated by TCF-1 binding to more distant cis-acting elements and/or by regulating the expression of additional trans-acting factors. Consistent with the observed differential, positive or negative role of TCF-1 for Ly-49 receptor acquisition, reporter gene assays revealed the presence of an inducing as well as a repressing TCF site in certain proximal Ly-49 promoters. These findings reveal an important role of TCF-1 for the formation of the NK cell receptor repertoire.
5' Untranslated Regions/analysis, 5' Untranslated Regions/isolation &, purification, Animals, Antigens, Ly, Base Sequence, Binding Sites/genetics, Binding Sites/immunology, Carrier Proteins/genetics, Carrier Proteins/metabolism, Cells, Cultured, DNA-Binding Proteins/deficiency, DNA-Binding Proteins/genetics, Histocompatibility Antigens Class I/genetics, Histocompatibility Antigens Class I/metabolism, Killer Cells, Natural/metabolism, Lectins, C-Type, Lymphoid Enhancer-Binding Factor 1, Membrane Glycoproteins/genetics, Membrane Glycoproteins/metabolism, Membrane Proteins/genetics, Membrane Proteins/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Peptide Fragments/genetics, Peptide Fragments/metabolism, Promoter Regions, Genetic/immunology, Receptors, Immunologic/genetics, Receptors, Immunologic/metabolism, Receptors, NK Cell Lectin-Like, T Cell Transcription Factor 1, Transcription Factors/deficiency, Transcription Factors/genetics, Tumor Cells, Cultured
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