Regulation of MHC class I expression by Foxp3 and its effect on regulatory T cell function

J Immunol. 2014 Mar 15;192(6):2892-903. doi: 10.4049/jimmunol.1302847. Epub 2014 Feb 12.

Abstract

Expression of MHC class I molecules, which provide immune surveillance against intracellular pathogens, is higher on lymphoid cells than on any other cell types. In T cells, this is a result of activation of class I transcription by the T cell enhanceosome consisting of Runx1, CBFβ, and LEF1. We now report that MHC class I transcription in T cells also is enhanced by Foxp3, resulting in higher levels of class I in CD4(+)CD25(+) T regulatory cells than in conventional CD4(+)CD25(-) T cells. Interestingly, the effect of Foxp3 regulation of MHC class I transcription is cell type specific: Foxp3 increases MHC class I expression in T cells but represses it in epithelial tumor cells. In both cell types, Foxp3 targets the upstream IFN response element and downstream core promoter of the class I gene. Importantly, expression of MHC class I contributes to the function of CD4(+)CD25(+) T regulatory cells by enhancing immune suppression, both in in vitro and in vivo. These findings identify MHC class I genes as direct targets of Foxp3 whose expression augments regulatory T cell function.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Base Sequence
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation / immunology*
  • HeLa Cells
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Jurkat Cells
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Promoter Regions, Genetic / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Nucleic Acid
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Thymocytes / immunology
  • Thymocytes / metabolism
  • beta 2-Microglobulin / deficiency
  • beta 2-Microglobulin / genetics
  • beta 2-Microglobulin / immunology

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Histocompatibility Antigens Class I
  • beta 2-Microglobulin