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Overexpression of Methyl-CpG Binding Protein 2 Impairs TH1 Responses

Duplication of the MECP2 gene in humans and mice results in immune dysregulation due in part to the suppression of IFN-γ production from T helper cells. The Immune Response in a Bind Children with MeCP2 (methyl-CpG binding protein 2) duplication syndrome have severe neurological defects caused by the overexpression of the MECP2 gene, which modulates expression of genes that influence neuronal and brain function. Many of these children also have recurrent respiratory infections; however, the role of MECP2 duplication in the immune system has been unclear. Now, Yang et al. have found that MeCP2 duplication may affect T helper type 1 (TH1) immunity. The authors examined patients with MECP2 duplication and found immunological abnormalities, including differences in memory T and B cells and NK cells. Indeed, mice that overexpress MeCP2 had an immunological defect as well. The immune system has evolved specialized functions to ward off particular types of infections. These MeCP2-overexpressing mice could not mount a sufficient TH1 response to control an infection by the parasite Leishmania major but could fight off an airway fungal infection—a TH2 response. Immune cells from children with MeCP2 duplication syndrome also had defects in the interferon-γ–mediated TH1 response. Yang et al. show that this defect may be caused by MeCP2-suppressing expression of IFN-γ in TH1 cells. This study paves the way for preventing infectious complications in children with MeCP2 duplication syndrome. 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 (TH2)–dependent allergic responses. Relative to normal T cells, TH cells from children and mice with MECP2 duplication displayed similar impairments in IFN-γ secretion and TH1 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 TH 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.