The N-terminal domain of NLRC5 confers transcriptional activity for MHC class I and II gene expression

J Immunol. 2014 Sep 15;193(6):3090-100. doi: 10.4049/jimmunol.1401065. Epub 2014 Aug 15.


Ag presentation to CD4(+) and CD8(+) T cells depends on MHC class II and MHC class I molecules, respectively. One important regulatory factor of this process is the transcriptional regulation of MHC gene expression. It is well established that MHC class II transcription relies on the NLR protein CIITA. Recently, another NLR protein, NLRC5, was shown to drive MHC class I expression. The molecular mechanisms of the function of NLRC5 however remain largely elusive. In this study, we present a detailed functional study of the domains of NLRC5 revealing that the N-terminal domain of human NLRC5 has intrinsic transcriptional activity. Domain swapping experiments between NLRC5 and CIITA showed that this domain contributes to MHC class I and MHC class II gene expression with a bias for activation of MHC class I promoters. Delivery of this construct by adeno-associated viral vectors upregulated MHC class I and MHC class II expression in human cells and enhanced lysis of melanoma cells by CD8(+) cytotoxic T cells in vitro. Taken together, this work provides novel insight into the function of NLRC5 and CIITA in MHC gene regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dependovirus / genetics
  • Gene Expression
  • Gene Expression Regulation
  • Genetic Vectors / genetics
  • HEK293 Cells
  • HeLa Cells
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class II / genetics*
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology
  • Mice
  • Nuclear Proteins / genetics
  • Promoter Regions, Genetic
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Trans-Activators / genetics
  • Transcriptional Activation / genetics*


  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II
  • Intracellular Signaling Peptides and Proteins
  • MHC class II transactivator protein
  • NLRC5 protein, human
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • Trans-Activators