Functional redundancy of transcription factor-binding sites in the killer cell Ig-like receptor (KIR) gene promoter

Steven R. Presnell, Lei Zhang, Cecilia A. Ramilo, Huei Wei Chan, Charles T. Lutz

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Variegated expression of inhibitory killer cell Ig-like receptors (KIRs) for MHC class I molecules helps NK cells distinguish normal from aberrant self and avoid autoreactivity. Prior studies of KIR promoters have produced conflicting results and no cis -acting sites have been independently confirmed. We took a comprehensive linker-scanning mutagenesis approach and substituted 24 consecutive 10-bp segments in the human KIR3DL1 promoter. Our analysis revealed eight segments that activated and three segments that repressed KIR transcription. Site-directed mutagenesis and electrophoretic mobility shift assays indicated that optimal KIR transcription requires a proximal Ets site that binds several Ets family members, a cAMP response element (CRE), a Runx site and a site that mediates complex interactions between Ets family members, signal transducer and activator of transcription 5 (STAT5) and YY1; Sp1 also contributes to KIR transcription. KIR transcription was greatly reduced by several compound mutations and was abrogated by a combination of mutations that affected the proximal Ets site, and the CRE, Runx, Sp1 and Ets/STAT sites. The many transcription factors that contribute to KIR transcription are partially redundant in the setting of transient transfection assays, helping to explain why only 0-2 activating sites had been reported in each of three prior studies. We propose that the multiplicity of transcription factors enables NK cells to sustain continuous KIR expression in diverse cellular and cytokine milieus, thus preventing NK autoreactivity.

Original languageEnglish
Pages (from-to)1221-1232
Number of pages12
JournalInternational Immunology
Issue number8
StatePublished - Aug 2006

Bibliographical note

Funding Information:
We thank Charlotte Kaetzel, John Yannelli, Liya Gu and Guo-Min Li for use of equipment. We thank Mikel Moore, Maria Bruno, Charlotte Kaetzel, Brett Spear, Andy Russo, Stephen Smale and Philip Marsden for discussion and advice. Steve Anderson shared advice and unpublished data. We are grateful to John Trowsdale, Dennis Watson, Junji Yodoi and Warren Leonard for gifts of DNA constructs or cells. The work was supported by NIH grant R01 AI50656.


  • Gene regulation
  • Human
  • Molecular biology
  • NK cells
  • Transcription factors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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