Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 29, Pages E3883-E3892Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1501662112
Keywords
tuberculosis; lncRNA; CD8(+) T cells
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Funding
- AMP
- oacute
- National Natural Science Foundation of China-National Institutes of Health (NSFC-NIH) Biomedical Collaborative Research Program Grant [81361120379]
- NSFC Grant [31170847]
- Guangzhou Municipality Commission for Science and Technology Innovation (Pearl River S&T Nova Program) Grant [201506010034]
- Guangdong Innovative R&D Team Program Grant [2009010058]
- United States-China Collaborative Research Program Grants [NIH AI106590, NSFC 31129002]
- NIH R01 Grants [HL64560, OD015092 (RR13601), AI106590]
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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-gamma and TNF-alpha. 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-gamma/TNF-alpha 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.
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