Polymerase III transcription is necessary for T cell priming by dendritic cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-11, Vol.116 (45), p.22721-22729
• Main Authors: Reverendo, Marisa, Argüello, Rafael J., Polte, Christine, Valečka, Jan, Camosseto, Voahirana, Auphan-Anezin, Nathalie, Ignatova, Zoya, Gatti, Evelina, Pierre, Philippe
• Format: Article
• Language: English
• Subjects: Animals; Antigen presentation; Antigen processing; Antigens; Biological Sciences; Casein; Casein kinase II; Casein Kinase II - metabolism; CD86 antigen; Cell activation; Cell proliferation; Cells, Cultured; Costimulator; Cytokines; Dendritic cells; Dendritic Cells - immunology; DNA-directed RNA polymerase; Enzyme Activation; Exposure; Female; Gene expression; Homology; Immunology; Inflammation; Interferon; Kinases; Life Sciences; Lipopolysaccharides; Lymphocytes; Lymphocytes T; Mice; Nuclear transport; Phosphorylation; PNAS Plus; Poly (I:C); Priming; Protein biosynthesis; Protein synthesis; Proteins; Rapamycin; Receptors; Ribonucleic acid; RNA; RNA polymerase; RNA Polymerase III - genetics; RNA Polymerase III - metabolism; RNA, Transfer - metabolism; Signal Transduction; T-Lymphocytes - immunology; Toll-like receptors; Toll-Like Receptors - metabolism; TOR protein; Transcription; Transcription, Genetic; tRNA
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1904396116

Exposure to microbe-associated molecular patterns (MAMPs) causes dendritic cells (DCs) to undergo a remarkable activation process characterized by changes in key biochemical mechanisms. These enhance antigen processing and presentation, as well as strengthen DC capacity to stimulate naïve T cell proliferation. Here, we show that in response to the MAMPS lipopolysaccharide and polyriboinosinic:polyribocytidylic acid (Poly I:C), RNA polymerase III (Pol lII)-dependent transcription and consequently tRNA gene expression are strongly induced in DCs. This is in part caused by the phosphorylation and nuclear export of MAF1 homolog negative regulator of Poll III (MAF1), via a synergistic casein kinase 2 (CK2)- and mammalian target of rapamycin-dependent signaling cascade downstream of Toll-like receptors (TLRs). De novo tRNA expression is necessary to augment protein synthesis and compensate for tRNA degradation driven by TLR-dependent DC exposure to type-I IFN. Although protein synthesis is not strongly inhibited in absence of RNA Pol III activity, it compromises the translation of key DC mRNAs, like those coding for costimulatory molecules and proinflammatory cytokines, which instead can be stored in stress granules, as shown for CD86 mRNA. TLR-dependent CK2 stimulation and subsequent RNA Pol III activation are therefore key for the acquisition by DCs of their unique T cell immunestimulatory functions.