Regulation of interferon-gamma during innate and adaptive immune responses.
Interferon-gamma (IFN-gamma) is crucial for immunity against intracellular pathogens and for tumor control. However, aberrant IFN-gamma expression has been associated with a number of autoinflammatory and autoimmune diseases. This cytokine is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by Th1 CD4 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops. Herein, we briefly review the functions of IFN-gamma, the cells that produce it, the cell extrinsic signals that induce its production and influence the differentiation of naïve T cells into IFN-gamma-producing effector T cells, and the signaling pathways and transcription factors that facilitate, induce, or repress production of this cytokine. We then review and discuss recent insights regarding the molecular regulation of IFN-gamma, focusing on work that has led to the identification and characterization of distal regulatory elements and epigenetic modifications with the IFN-gamma locus (Ifng) that govern its expression. The epigenetic modifications and three-dimensional structure of the Ifng locus in naive CD4 T cells, and the modifications they undergo as these cells differentiate into effector T cells, suggest a model whereby the chromatin architecture of Ifng is poised to facilitate either rapid opening or silencing during Th1 or Th2 differentiation, respectively.
Schoenborn
Jamie R
JR
Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA.
Wilson
Christopher B
CB
D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D007371:Interferon-gamma