Summary
Epigenetic changes, including histone methylation, control T cell differentiation and memory formation, though the enzymes that mediate these processes are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, supports T follicular helper (Tfh) cell responses that are essential for B cell antibody generation and the resolution of chronic viral infections. Mice with a T cell-specific UTX deletion had fewer Tfh cells, reduced germinal center responses, lacked virus-specific IgG, and were unable to resolve chronic lymphocytic choriomeningitis virus infections. UTX-deficient T cells showed decreased expression of interleukin-6 receptor-α and other Tfh cell-related genes that were associated with increased H3K27 methylation. Additionally, Turner Syndrome subjects, who are predisposed to chronic ear infections, had reduced UTX expression in immune cells and decreased circulating CD4+ CXCR5+ T cell frequency. Thus, we identify a critical link between UTX in T cells and immunity to infection.
OBJECTIVEType 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes.RESEARCH DESIGN AND METHODSWe adoptively transferred HLA-A2–matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γcnull/HLA-A*0201 (NOD-scid/γcnull/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/γcnull/A2 mice after transfer.RESULTSHuman T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/γcnull/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γcnull/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2–matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8+ T cells among the islet infiltrates.CONCLUSIONSWe show that insulitis is transferred to NOD-scid/γcnull/A2 mice that received HLA-A2–matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8+ T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γcnull/A2 mice transferred with HLA-A2–matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell–mediated responses in patients with type 1 diabetes.
T cell differentiation and memory formation are impacted by epigenetic changes that modulate nucleosome structure to regulate transcription factor accessibility. The enzymes and specific targets that mediate these processes within T cells are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, promotes the formation of the CD4+ T follicular helper cell (Tfh) phenotype during a chronic virus infection. Mice with T cell specific UTX deletion had defects in Tfh cell generation and function that resulted in reduced germinal center responses and virus-specific immunoglobulin production. Furthermore, clearance of the chronic virus infection was specifically dependent on T cell expression of UTX. H3K27me3-ChIP-sequencing and RNA expression analysis revealed a subset of genes that were specifically regulated by UTX via H3K27 demethylation. This group included IL-6Ra, a known regulator of Tfh responses, as well as other genes, which are potentially novel Tfh effector genes. Thus, we identify a critical link between UTX-dependent H3K27 demethylase activity in T cells and immunity to infection.
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