The Chromatin-Modifying Enzyme Ezh2 Is Critical for the Maintenance of Regulatory T Cell Identity after Activation

Abstract

SUMMARY Regulatory T cells (Treg cells) are required for immune homeostasis. Chromatin remodeling is essential for establishing diverse cellular identities, but how the epigenetic program in Treg cells is maintained throughout the dynamic activation process remains unclear. Here we have shown that CD28 co-stimulation, an extracellular cue intrinsically required for Treg cell maintenance, induced the chromatin-modifying enzyme, Ezh2. Treg-specific ablation of Ezh2 resulted in spontaneous autoimmunity with reduced Foxp3+ cells in non-lymphoid tissues and impaired resolution of experimental autoimmune encephalomyelitis. Utilizing a model designed to selectively deplete wild-type Treg cells in adult mice co-populated with Ezh2-deficient Treg cells, Ezh2-deficient cells were destabilized and failed to prevent autoimmunity. After activation, the transcriptome of Ezh2-deficient Treg cells was disrupted, with altered expression of Treg cell lineage genes in a pattern similar to Foxp3-deficient Treg cells. These studies reveal a critical role for Ezh2 in the maintenance of Treg cell identity during cellular activation.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…In addition, T reg cells can be converted into T H 17 cells in the presence of IL-6 and TGF-β 46,47 , which might underlie certain forms of autoimmunity, such as autoimmune hepatitis and psoriasis 48,49 , and CXCL11 promotes T reg cell differentiation into CXCR3 + CD4 + effector T cells, suggesting that it might be involved in the development of autoimmune encephalitis 50 . Control of T reg cell plasticity is further regulated by EZH2, a target for multiple small-molecule inhibitors in cancer trials 51 . EZH2 is a histone modifier that functions as the catalytic component of the polycomb repressive complex 2 (PRC2).…”

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

“…HDAC inhibitors upregulate MHCI antigen presentation of natural killer (NK) ligands on tumor cells but may have repressive effects on other immune subsets (64). Polycomb repression of chromatin, linked to neoplastic processes in Ewing, synovial, and rhabdomyosarcomas is also critical for stable lineage commitments and T-cell tolerance, with loss of function contributing to depletion of regulatory T cells and activation of effector T cells (65,66). Thus, relations between emerging immunotherapies, epigenetic drugs, tyrosine kinase inhibitors, and cytotoxic agents will be complex, requiring further animal model studies and clinical trials to determine the best combinatorial approaches.…”

Mutation Spectra of Histone Methyltransferases With Canonical SET Domains and EZH2-Targeted Therapy

“…EZH2 and FOXP3 are both involved in the inhibition of autoimmunity and antitumor immunity by Treg cells [129,130], whereas EZH2 itself is involved in the resistance of tumor cells to chemotherapy [111,113] and radiotherapy [131]. Preclinical studies indicate that EZH2 inhibitors are applicable for cancer chemotherapy in combination with other anticancer drugs, such as topoisomerase II inhibitor [111], EGFR inhibitor [132], VEGFR2 inhibitor [133] or HDAC inhibitor [134].…”