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Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland
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
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.
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 F. Stevenaert, K. Van Beneden, V. De Colvenaer, A. S. Franki, V. Debacker, T. Boterberg, D. Deforce, K. Pfeffer, J. Plum, D. Elewaut, et al. Ly49 and CD94/NKG2 receptor acquisition by NK cells does not require lymphotoxin-{beta} receptor expression Blood, August 1, 2005; 106(3): 956 - 962. [Abstract] [Full Text] [PDF]
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V. Ioannidis, B. Kunz, D. M. Tanamachi, L. Scarpellino, and W. Held Initiation and Limitation of Ly-49A NK Cell Receptor Acquisition by T Cell Factor-1 J. Immunol., July 15, 2003; 171(2): 769 - 775. [Abstract] [Full Text] [PDF]
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C. A. Stewart, J. van Bergen, and J. Trowsdale Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters J. Immunol., June 15, 2003; 170(12): 6073 - 6081. [Abstract] [Full Text] [PDF]
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