Von Wiedergängern und anderen Zeitgenossen. zur Prosa Gyrdir Elíassons

NK cells play a critical role in host defense against viruses. In this study, we investigated the role of NKG2D in the expansion of NK cells after mouse CMV (MCMV) infection. Wild-type and NKG2D-deficient (Klrk1-/- ) Ly49H+ NK cells proliferated robustly when infected with MCMV strains engineered to allow expression of NKG2D ligands, which enhanced the response of wild-type NK cells. Naive NK cells exclusively express NKG2D-L, which pairs only with DAP10, whereas NKG2D-S expressed by activated NK cells pairs with DAP10 and DAP12, similar to Ly49H. However, NKG2D alone was unable to drive robust expansion of Ly49H- NK cells when mice were infected with these MCMV strains, likely because NKG2D-S was only transiently expressed postinfection. These findings demonstrate that NKG2D augments Ly49H-dependent proliferation of NK cells; however, NKG2D signaling alone is inadequate for expansion of NK cells, likely due to only transient expression of the NKG2D-DAP12 complex

Inositol phosphatase INPP4B sustains ILC1s and intratumoral NK cells through an AKT-driven pathway

Innate lymphoid cells (ILCs) are a heterogeneous population of lymphocytes that coordinate early immune responses and maintain tissue homeostasis. Type 1 innate immune responses are mediated by natural killer (NK) cells and group 1 ILCs (ILC1s). Despite their shared features, NK cells and ILC1s display profound differences among various tissue microenvironments. Here, we identify the inositol polyphosphatase INPP4B as a hallmark feature of tissue-resident ILC1s and intratumoral NK cells using an scRNA-seq atlas of tissue-associated and circulating NK/ILC1s. Conditional deletion of Inpp4b in ILC1s and NK cells reveals that it is necessary for the homeostasis of tissue-resident ILC1s but not circulating NK cells at steady-state. Inpp4b-deficient cells display increased rates of apoptosis and reduced activation of the prosurvival molecule AKT. Furthermore, expression of Inpp4b by NK/ILC1s is necessary for their presence in the intratumoral environment, and lack of Inpp4b impairs antitumor immunity. These findings highlight INPP4B as a novel regulator of tissue residency and antitumor function in ILC1s and NK cells

Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription

Group 3 innate lymphoid cells (ILC3s) are RORγ

Cutting Edge: NKG2D Signaling Enhances NK Cell Responses but Alone Is Insufficient To Drive Expansion during Mouse Cytomegalovirus Infection.

NK cells play a critical role in host defense against viruses. In this study, we investigated the role of NKG2D in the expansion of NK cells after mouse CMV (MCMV) infection. Wild-type and NKG2D-deficient (Klrk1-/- ) Ly49H+ NK cells proliferated robustly when infected with MCMV strains engineered to allow expression of NKG2D ligands, which enhanced the response of wild-type NK cells. Naive NK cells exclusively express NKG2D-L, which pairs only with DAP10, whereas NKG2D-S expressed by activated NK cells pairs with DAP10 and DAP12, similar to Ly49H. However, NKG2D alone was unable to drive robust expansion of Ly49H- NK cells when mice were infected with these MCMV strains, likely because NKG2D-S was only transiently expressed postinfection. These findings demonstrate that NKG2D augments Ly49H-dependent proliferation of NK cells; however, NKG2D signaling alone is inadequate for expansion of NK cells, likely due to only transient expression of the NKG2D-DAP12 complex

Dual Analysis of the Murine Cytomegalovirus and Host Cell Transcriptomes Reveal New Aspects of the Virus-Host Cell Interface

<div><p>Major gaps in our knowledge of pathogen genes and how these gene products interact with host gene products to cause disease represent a major obstacle to progress in vaccine and antiviral drug development for the herpesviruses. To begin to bridge these gaps, we conducted a dual analysis of Murine Cytomegalovirus (MCMV) and host cell transcriptomes during lytic infection. We analyzed the MCMV transcriptome during lytic infection using both classical cDNA cloning and sequencing of viral transcripts and next generation sequencing of transcripts (RNA-Seq). We also investigated the host transcriptome using RNA-Seq combined with differential gene expression analysis, biological pathway analysis, and gene ontology analysis.</p><p>We identify numerous novel spliced and unspliced transcripts of MCMV. Unexpectedly, the most abundantly transcribed viral genes are of unknown function. We found that the most abundant viral transcript, recently identified as a noncoding RNA regulating cellular microRNAs, also codes for a novel protein. To our knowledge, this is the first viral transcript that functions both as a noncoding RNA and an mRNA. We also report that lytic infection elicits a profound cellular response in fibroblasts. Highly upregulated and induced host genes included those involved in inflammation and immunity, but also many unexpected transcription factors and host genes related to development and differentiation. Many top downregulated and repressed genes are associated with functions whose roles in infection are obscure, including host long intergenic noncoding RNAs, antisense RNAs or small nucleolar RNAs. Correspondingly, many differentially expressed genes cluster in biological pathways that may shed new light on cytomegalovirus pathogenesis. Together, these findings provide new insights into the molecular warfare at the virus-host interface and suggest new areas of research to advance the understanding and treatment of cytomegalovirus-associated diseases.</p></div

Analysis of the novel most abundant MCMV transcript and protein.

<p>(A) Comparison of RNA-Seq data and the longest MAT cDNA clone (E125) with current annotation (GU305914). The predicted exons are shown in white boxes. (B) Predicted amino acid sequence of the MAT protein. The first 127 residues match a truncated m169 translation and the C-terminal 20 residues highlighted in gray are derived from exon 2, mapping to the m168 gene. (C) Northern analysis of MAT RNA in MEF cells infected with various deletion mutants. Note that the single gene mutants are partial gene deletions and thus truncated transcripts accumulate. (D) Immunoblot analysis of MEF cell lysates probed with monoclonal antibody generated to the predicted m169 ORF or monoclonal antibody to actin (45 kDa band). (E) Immunoblot analysis of the time course of MAT protein accumulation in infected cells and (F) quantitation. (G) Immunoblot analysis of MAT protein from cells exposed to wild virus isolates. (H) MAT protein accumulation in WT and m168mut virus infected Balb/c MEF. Mutation of the binding site for miR27-b in MAT 3′UTR did not alter regulation of MAT protein expression.</p

Top 20 host genes¹ downregulated in infection.

1<p>p<0.05 identified using SAMMate with EdgeR.</p><p>Genes associated with genetic networks identified by IPA are shown in bold.</p>2<p>antisense transcripts.</p>3<p>recently withdrawn from Mouse Genome Informatics (MGI) database.</p>4<p>uncharacterized RNA.</p>5<p>lincRNA.</p>6<p>microRNA record discontinued.</p

Comparison of cDNA cloning and RNA-Seq data in relation to current genome annotation.

<p>Comparison of poly(A) cDNA library (green arrows) and RNA-Seq analysis of murine cytomegalovirus (gray histograms). The longest clone from each group of clones in the cDNA library is shown. ELAND alignments of RNA-Seq reads were loaded in Integrative Genomics Viewer and compared to NC_004065.1, (red arrows) and GU305914.1 (blue arrows). The data range for RNA-Seq data was set to 20–5000. Data is shown in 30 kb ranges with 1 kb overlap. Data is shown for the first 120 kb of the MCMV genome and the figure legend is shown in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003611#ppat-1003611-g002" target="_blank">Figure 2</a>.</p

Gene enrichment analysis of differentially regulated mouse genes in MCMV infection.

<p>Differentially expressed genes were identified by SAMMate and analyzed with IPA Core Analysis with fold change ratio cutoff of 2. Shown are top diseases and disorders, molecular and cellular functions, and physiological system development and functions (A) and top canonical pathways (B) of DE genes.</p