Autoimmunity induced by epigenome alteration affecting thymic Treg cell development

Abstract

Methyl-CpG-binding domain protein 3 (MBD3), an essential component of the nucleosome remodeling and deacetylase (NuRD) complex, controls chromatin accessibility at lineage-specific transcriptional enhancers and promoters during hematopoietic cell differentiation. Here, we have shown that MBD3 deficiency in the T cell compartment resulted in spontaneous development of T cell–mediated multiorgan autoimmune diseases including fatal autoimmune myocarditis. The MBD3-deficient mice notably showed a significant reduction of CD25 + Foxp3 + regulatory T (Treg) cells in both the thymus and periphery without much affecting the development and function of conventional T (Tconv) cells. Mixed bone marrow (BM) chimeras reconstituted with wild-type and MBD3-deficient BM revealed a cell-intrinsic defect in thymic Treg cell lineage differentiation in MBD3-deficient cells. Transcriptional, phenotypic, and functional analyses of thymocyte subsets further revealed that MBD3 deficiency particularly affected the activation of a Treg-specific enhancer of the Il2ra gene encoding CD25, hence impaired CD25 expression in immature CD4 single-positive thymocytes (ImCD4SP) but not in peripheral T cells. The impairment markedly limited thymic Treg precursor cell generation and substantially reduced overall thymic Treg cell output. By contrast, MBD3 deficiency scarcely impacted the TGF-β/IL-2-dependent in vitro Treg cell generation from Tconv cells. Thus, Treg-specific developmental properties such as high IL-2/CD25 dependency of their thymic differentiation may render them more sensitive than Tconv cells to epigenetic changes of the whole T cell compartment. The results provide a mechanistic basis by which general epigenomic alterations in the T cell compartment can be causative of autoimmune and other immunological diseases through selectively affecting thymic Treg cell development.