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

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.tuberculosis | lncRNA | CD8 + T cells

Microarray analysis of long noncoding RNA and mRNA expression profiles in human macrophages infected with Mycobacterium tuberculosis

“…Wang, Y. et al . reported that lncRNA-CD244 acted as an epigenetic regulator of IFN-γ and TNF-α production in CD8 + T cells and that it impacts CD8 + T cell immunity against active Mtb infection31. LncRNA-MEG3, which is shown to be a tumour suppressor gene, was downregulated in macrophages with BCG infection, leading to the induction of autophagy and enhanced eradication of intracellular pathogens32.…”

A Long Journey Ahead: Long Non-coding RNAs in Bacterial Infections

“…It was shown that the lncRNA-CD244 which is upregulated by the T-cell inhibitory molecule CD244 in M. tuberculosis infection acts as an epigenetic inhibitor of TNF-α and INF-γ expression. The authors were able to show that lncRNA-CD244 directly interacts with the PCR2 subunit EZH2 which leads to trimethylation of H3K27 and a more repressive chromatin state at the INF-γ or TNF-α loci (Wang et al, 2015). A similar mechanism in terms of lncRNA-mediated control of TNF expression has been reported through bidirectional lncRNAs upstream of the TNF gene locus (Shi et al, 2014).…”

NKG2D Promotes B1a Cell Development and Protection against Bacterial Infection

“…Nevertheless, similar to NKG2D, CD244 deficiency results in a reduction of B1a cells in the peritoneal cavity (12), although its effects on B cell development appear to be more pleiotropic than those of NKG2D. Moreover, CD244 is able to regulate immune cell function through epigenetic silencing of chromatin regions (39). We propose that NKG2D might similarly control loci that are important for B1a cell development.…”