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Overexpression of methyl-CpG binding protein 2 impairs T(H)1 responses.

The DNA binding protein methyl-CpG binding protein 2 (MeCP2) critically influences neuronal and brain function by modulating gene expression, and children with overexpression of the MECP2 gene exhibit postnatal neurological syndromes. We demonstrate that some children with MECP2 duplication also display variable immunological abnormalities that include reductions in memory T and B cells and natural killer cells and immunoglobulin assay responses. Moreover, whereas mice with MeCP2 overexpression were unable to control infection with the intra-macrophage parasite Leishmania major and secrete interferon-γ (IFN-γ) from involved lymph nodes, they were able to control airway fungal infection by Aspergillus niger and mount protective T helper cell type 2 (T(H)2)-dependent allergic responses. Relative to normal T cells, T(H) cells from children and mice with MECP2 duplication displayed similar impairments in IFN-γ secretion and T(H)1 responses that were due to both MeCP2-dependent suppression of IFN-γ transcription and sequestration of the IFN-γ locus as assessed by chromatin immunoprecipitation assay. Thus, overexpressed MeCP2 aberrantly suppresses IFN-γ secretion from T(H) cells, potentially leading to a partially immunodeficient state. Our findings establish a rational basis for identifying, treating, and preventing infectious complications potentially affecting children with MECP2 duplication.

Pubmed ID: 23220634

Authors

  • Yang T
  • Ramocki MB
  • Neul JL
  • Lu W
  • Roberts L
  • Knight J
  • Ward CS
  • Zoghbi HY
  • Kheradmand F
  • Corry DB

Journal

Science translational medicine

Publication Data

December 5, 2012

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI057696
  • Agency: NIAID NIH HHS, Id: AI070973
  • Agency: NICHD NIH HHS, Id: HD024064
  • Agency: NHLBI NIH HHS, Id: HL75243
  • Agency: NHLBI NIH HHS, Id: K02 HL075243
  • Agency: NINDS NIH HHS, Id: NS057819
  • Agency: NINDS NIH HHS, Id: NS062711
  • Agency: NICHD NIH HHS, Id: P30 HD024064
  • Agency: NIAID NIH HHS, Id: R01 AI057696
  • Agency: NICHD NIH HHS, Id: R01 HD062553
  • Agency: NINDS NIH HHS, Id: R01 NS057819
  • Agency: NIAID NIH HHS, Id: U19 AI070973
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Flow Cytometry
  • Gene Duplication
  • Humans
  • Interferon-gamma
  • Leishmania major
  • Leishmaniasis, Cutaneous
  • Methyl-CpG-Binding Protein 2
  • Mice
  • RNA, Small Interfering
  • Th1 Cells