Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection

Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):E3883-92. doi: 10.1073/pnas.1501662112. Epub 2015 Jul 6.

Abstract

Molecular mechanisms for T-cell immune responses modulated by T cell-inhibitory molecules during tuberculosis (TB) infection remain unclear. Here, we show that active human TB infection up-regulates CD244 and CD244 signaling-associated molecules in CD8(+) T cells and that blockade of CD244 signaling enhances production of IFN-γ and TNF-α. CD244 expression/signaling in TB correlates with high levels of a long noncoding RNA (lncRNA)-BC050410 [named as lncRNA-AS-GSTT1(1-72) or lncRNA-CD244] in the CD244(+)CD8(+) T-cell subpopulation. CD244 signaling drives lncRNA-CD244 expression via sustaining a permissive chromatin state in the lncRNA-CD244 locus. By recruiting polycomb protein enhancer of zeste homolog 2 (EZH2) to infg/tnfa promoters, lncRNA-CD244 mediates H3K27 trimethylation at infg/tnfa loci toward repressive chromatin states and inhibits IFN-γ/TNF-α expression in CD8(+) T cells. Such inhibition can be reversed by knock down of lncRNA-CD244. Interestingly, adoptive transfer of lncRNA-CD244-depressed CD8(+) T cells to Mycobacterium tuberculosis (MTB)-infected mice reduced MTB infection and TB pathology compared with lncRNA-CD244-expressed controls. Thus, this work uncovers previously unidentified mechanisms in which T cell-inhibitory signaling and lncRNAs regulate T-cell responses and host defense against TB infection.

Keywords: CD8+ T cells; lncRNA; tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antigens, CD
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Chromatin / metabolism
  • Computational Biology
  • Conserved Sequence
  • Enhancer of Zeste Homolog 2 Protein
  • Epigenesis, Genetic* / drug effects
  • Evolution, Molecular
  • Gene Knockdown Techniques
  • Genome, Human
  • HEK293 Cells
  • Humans
  • Immunity* / drug effects
  • Immunity* / genetics
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Models, Biological
  • Polycomb Repressive Complex 2 / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • RNA, Long Noncoding / genetics*
  • Receptors, Immunologic
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • Transcription Factors / metabolism
  • Tuberculosis / immunology*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Up-Regulation / drug effects

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • CD244 protein, human
  • Chromatin
  • Intracellular Signaling Peptides and Proteins
  • RNA, Long Noncoding
  • Receptors, Immunologic
  • SH2D1A protein, human
  • SH2D1B protein, human
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2