Overexpression of Methyl-CpG Binding Protein 2 Impairs T _H 1 Responses

Abstract

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.

Cytogenomic Delineation and Clinical Characterization of Three Cases of MECP2 Duplication Syndrome

“…All our patients had frequent hospitalizations for lower respiratory tract infections, with some episodes requiring invasive ventilation and intensive care admission. In a clinical study, T helper cells from children and mice with MECP2 duplication displayed impaired interferon-gamma secretion and T helper cell type 1 responses, suggesting a partially immunodeficient state [13]. This could explain the predisposition to recurrent respiratory infections.…”

MECP2 disorders: from the clinic to mice and back

“…Males with MDS exhibit infantile hypotonia, autistic features, gait abnormalities, seizures, and recurrent infections (5,(36)(37)(38)(39). The inclusion of IRAK1, which encodes IL receptor-associated kinase 1, in the duplicated region was hypothesized to mediate the immunological defects of the patients; however, recent work indicates that overexpression of MECP2 is sufficient to impair T cell function (40). Though approximately 40% of MDS males die before the age of 25 (41), again, females are more protected due to the presence of a WT X chromosome.…”

Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice

“…to 5-fold above normal, also demonstrate impaired IFN-γ levels during infection in vivo (7). This defect in IFN-γ production was hypothesized to account for the chronic infections seen in MeCP2 duplication syndrome (7).…”

“…It was previously shown that MeCP2 plays an important role in immune cells, including T cells (7)(8)(9)(10) and myeloid cells (11)(12)(13)(14)(15)(16), and thus it was hypothesized that chronic infections seen in MeCP2 duplication syndrome may be explained by the direct role of MeCP2 in immune cells. In 2012, Yang et al demonstrated that CD4 + T cells overexpressing MeCP2 in both mice and humans were deficient in IFN-γ production after skewing to Th1 in vitro, and that MeCP2 Tg3 mice (17), which have a human MeCP2 gene inserted into their genome and overexpress MeCP2 at levels 3-Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively.…”

“…This defect in IFN-γ production was hypothesized to account for the chronic infections seen in MeCP2 duplication syndrome (7). Importantly, Yang et al demonstrated that transfer of wildtype CD4 + T cells into MeCP2 Tg3 mice decreased footpad swelling and increased IFN-γ levels during Leishmania major infection (7), suggesting that CD4 + T cells expressing normal levels of MeCP2 have the potential to ameliorate immune pathology in an MeCP2-overexpressing host.…”