The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated selfantigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14 + Sirpα + population of monocytederived dendritic cells (CD14 + moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14 + moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25 + Foxp3 + Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14 + moDC, the generation of Tregs, and thereby the establishment of central tolerance.

The identity of peripheral Aire-expressing cells remains poorly understood. This study shows that Aire-expressing cells in peripheral lymph nodes exhibit typical ILC3 characteristics. These cells display potent APC features, suggesting a function in the control of T cell responses.

Article Virus-Induced Changes in mRNA Secondary Structure Uncover cis-Regulatory Elements that Directly Control Gene Expression Graphical Abstract Highlights d Mapping dynamic RNA structures provides a strategy to identify regulatory regions d Translation plays a major role in unwinding secondary structures in vivo d Structurally dynamic 3 0 UTRs are enriched in elements that regulate mRNA stability d CDS regions contain dynamic structural elements that regulate translation

Human herpesvirus-6 (HHV-6) A and B are ubiquitous betaherpesviruses, infecting the majority of the human population. They encompass large genomes and our understanding of their protein coding potential is far from complete. Here, we employ ribosome-profiling and systematic transcript-analysis to experimentally define HHV-6 translation products. We identify hundreds of new open reading frames (ORFs), including upstream ORFs (uORFs) and internal ORFs (iORFs), generating a complete unbiased atlas of HHV-6 proteome. By integrating systematic data from the prototypic betaherpesvirus, human cytomegalovirus, we uncover numerous uORFs and iORFs conserved across betaherpesviruses and we show uORFs are enriched in late viral genes. We identified three highly abundant HHV-6 encoded long non-coding RNAs, one of which generates a non-polyadenylated stable intron appearing to be a conserved feature of betaherpesviruses. Overall, our work reveals the complexity of HHV-6 genomes and highlights novel features conserved between betaherpesviruses, providing a rich resource for future functional studies.

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