ABSTRACT
The transcriptional programs that regulate CD8 T-cell differentiation and function in the context of viral infections or tumor immune surveillance have been extensively studied; yet how long noncoding RNAs (lncRNAs) and the loci that transcribe them contribute to the regulation of CD8 T cells during viral infections remains largely unexplored. Here, we report that transcription of the lncRNA Morrbid is specifically induced by T-cell receptor (TCR) and type I IFN stimulation during the early stages of acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. In response to type I IFN, the Morrbid RNA and its locus control CD8 T cell expansion, survival, and effector function by regulating the expression of the proapoptotic factor, Bcl2l11, and by modulating the strength of the PI3K-AKT signaling pathway. Thus, our results demonstrate that inflammatory cue-responsive lncRNA loci represent fundamental mechanisms by which CD8 T cells are regulated in response to pathogens and potentially cancer.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Lymphocytic Choriomeningitis/immunology , RNA, Long Noncoding/immunology , Animals , CD8-Positive T-Lymphocytes/virology , Cell Differentiation/immunology , Interferon Type I/immunology , Lymphocyte Activation/immunology , Lymphocytic Choriomeningitis/virology , Lymphocytic choriomeningitis virus/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Phosphatidylinositol 3-Kinases/immunology , Proto-Oncogene Proteins c-bcl-2/immunology , Receptors, Antigen, T-Cell/immunology , Signal Transduction/immunologyABSTRACT
The immune system is composed of diverse cell types that coordinate responses to infection and maintain tissue homeostasis. In each of these cells, extracellular cues determine highly specific epigenetic landscapes and transcriptional profiles to promote immunity while maintaining homeostasis. New evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in epigenetic and transcriptional regulation in mammals. Thus, lncRNAs have emerged as key regulatory molecules of immune cell gene expression programs in response to microbial and tissue-derived cues. We review here how lncRNAs control the function and homeostasis of cell populations during immune responses, emphasizing the diverse molecular mechanisms by which lncRNAs tune highly contextualized transcriptional programs. In addition, we discuss the new challenges faced in interrogating lncRNA mechanisms and function in the immune system.
