ABSTRACT
Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity.
Subject(s)
Enhancer of Zeste Homolog 2 Protein/metabolism , T-Lymphocytes, Regulatory/metabolism , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Enhancer of Zeste Homolog 2 Protein/deficiency , Enhancer of Zeste Homolog 2 Protein/genetics , Forkhead Transcription Factors/metabolism , Humans , Interferon-gamma/metabolism , Lymphocytes, Tumor-Infiltrating/cytology , Lymphocytes, Tumor-Infiltrating/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms/immunology , Neoplasms/pathology , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/immunology , Tumor Microenvironment , Tumor Necrosis Factor-alpha/metabolismABSTRACT
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.
Subject(s)
CD28 Antigens/immunology , Lymphocyte Activation/immunology , Polycomb Repressive Complex 2/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Autoimmunity/genetics , Autoimmunity/immunology , CD8-Positive T-Lymphocytes/immunology , Chromatin Assembly and Disassembly , Encephalomyelitis, Autoimmune, Experimental/immunology , Enhancer of Zeste Homolog 2 Protein , Female , Forkhead Transcription Factors/biosynthesis , Forkhead Transcription Factors/genetics , Gene Expression Regulation , Heparin-binding EGF-like Growth Factor/genetics , Immune Tolerance/genetics , Immune Tolerance/immunology , Lymphocyte Depletion , Mice , Mice, Inbred C57BL , Mice, Transgenic , Polycomb Repressive Complex 2/genetics , Promoter Regions, Genetic/genetics , T-Lymphocytes, Regulatory/cytologyABSTRACT
Foxp3(+) regulatory T cells (Treg cells) are required for immunological homeostasis. One notable distinction between conventional T cells (Tconv cells) and Treg cells is differences in the activity of phosphatidylinositol-3-OH kinase (PI(3)K); only Tconv cells downregulate PTEN, the main negative regulator of PI(3)K, upon activation. Here we found that control of PI(3)K in Treg cells was essential for lineage homeostasis and stability. Mice lacking Pten in Treg cells developed an autoimmune-lymphoproliferative disease characterized by excessive T helper type 1 (TH1) responses and B cell activation. Diminished control of PI(3)K activity in Treg cells led to reduced expression of the interleukin-2 (IL-2) receptor α subunit CD25, accumulation of Foxp3(+)CD25(-) cells and, ultimately, loss of expression of the transcription factor Foxp3 in these cells. Collectively, our data demonstrate that control of PI(3)K signaling by PTEN in Treg cells is critical for maintaining their homeostasis, function and stability.
