Natural killer (NK) cells are innate lymphocytes that lack antigen-specific rearranged receptors, a hallmark of adaptive lymphocytes. In some people infected with human cytomegalovirus (HCMV), an NK cell subset expressing the activating receptor NKG2C undergoes clonal-like expansion that partially resembles anti-viral adaptive responses. However, the viral ligand that drives the activation and differentiation of adaptive NKG2C NK cells has remained unclear. Here we found that adaptive NKG2C NK cells differentially recognized distinct HCMV strains encoding variable UL40 peptides that, in combination with pro-inflammatory signals, controlled the population expansion and differentiation of adaptive NKG2C NK cells. Thus, we propose that polymorphic HCMV peptides contribute to shaping of the heterogeneity of adaptive NKG2C NK cell populations among HCMV-seropositive people.

Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor‐specific mutations not only in protein‐coding sequences but also in non‐coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this “dark matter” of the genome. Malignancy‐driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5′‐UTR and 3′‐UTR. Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non‐coding RNA, such as microRNA, lncRNA, and lincRNA. A synonymous mutation changes the coding region in the DNA and RNA but not the protein sequence. Importantly, oncogenes such as TERT or miR‐21 as well as tumor suppressor genes such as TP53/p53,APC,BRCA1, or RB1 can be affected by these alterations. In summary, coding‐independent mutations can affect gene regulation from transcription, splicing, mRNA stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non‐coding or allegedly silent mutations in tumorigenesis.

Natural killer (NK) cells are lymphocytes that contribute to the early immune responses to viruses. NK cells are innate immune cells that do not express rearranged antigen receptors but sense their environment via receptors for pro-inflammatory cytokines, as well as via germline-encoded activating receptors specific for danger or pathogen signals. A group of such activating receptors is stochastically expressed by certain subsets within the NK cell compartment. After engagement of the cognate viral ligand, these receptors contribute to the specific activation and 'preferential' population expansion of defined NK cell subsets, which partially recapitulate some features of adaptive lymphocytes. In this Review, we discuss the numerous modes for the specific recognition of viral antigens and peptides by NK cells and the implications of this for the composition of the NK cell repertoire as well as for the the selection of viral variants.

Clonal expansion of cells with somatically diversified receptors and their long-term maintenance as memory cells is a hallmark of adaptive immunity. Here, we studied pathogen-specific adaptation within the innate immune system, tracking natural killer (NK) cell memory to human cytomegalovirus (HCMV) infection. Leveraging single-cell multiomic maps of ex vivo NK cells and somatic mitochondrial DNA mutations as endogenous barcodes, we reveal substantial clonal expansion of adaptive NK cells in HCMV+ individuals. NK cell clonotypes were characterized by a convergent inflammatory memory signature enriched for AP1 motifs superimposed on a private set of clone-specific accessible chromatin regions. NK cell clones were stably maintained in specific epigenetic states over time, revealing that clonal inheritance of chromatin accessibility shapes the epigenetic memory repertoire. Together, we identify clonal expansion and persistence within the human innate immune system, suggesting that these mechanisms have evolved independent of antigen-receptor diversification.

Angeborene lymphoide Zellen (ILCs, engl. für Innate Lymphoid Cells) bilden eine kürzlich beschriebene Familie von Effektorzellen des angeborenen Immunsystems, die in verschiedenste immunologische Prozesse involviert sind. ILCs fehlen somatisch rekombinierte Antigenrezeptoren und können aufgrund ihrer Master-Transkriptionsfaktoren und Effektorfunktionen in drei Hauptgruppen eingeteilt werden. In der Embryonalentwicklung spielt ein spezifisches Mitglied der Typ 3 ILCs, sogenannte LTi (engl. für Lymphoid Tissue inducer) Zellen, eine zentrale Rolle in der Entwicklung von Lymphknoten. Wie die gesamte ILC3 Familie, sind auch LTi Zellen abhängig von dem Master-Transkriptionsfaktor ROR t, was sich in ROR t-defizienten Mäuse nicht nur durch die Abwesenheit aller ILC3, sondern makroskopisch auch durch fehlende Lymphknoten äußert. ILC3 persistieren bis ins Erwachsenenalter und befinden sich hauptsächlich im Darmgewebe und den assoziierten mesenterialen Lymphknoten, wo sie die Homöostase der Barrierefunktionen, Immunüberwachung, sowie die Typ-3-Gewebeimmunität unterstützen. Während postnatale Ko-expression der Transkriptionsfaktoren T-bet und ROR t in spezifischen ILC3-Subpopulationen und deren Bedeutung für Differenzierung, Phänotyp und Funktionen fest etabliert sind, ist der Einfluss von T-bet in fötalen ILC3 und auf die Generation von Lymphknoten noch unbekannt. Um diese Mechanismen genau zu untersuchen, wurden fötale ILCs mittels Einzelzell-RNA-Sequenzierung detailliert charakterisiert, wodurch eine unerwartete Heterogenität innerhalb der ILC3 mit T-bet-exprimierenden Zellen aufgedeckt wurde. Außerdem wurden PLZF + ILC-Vorläufer (ILCP, engl. für Innate Lymphoid Cell Precursor) im sich entwickelnden Darm nachgewiesen, was darauf hindeutet, dass der embryonale Darm eine aktive Differenzierungsnische für ILCs während der frühen Entwicklung darstellt. Weiterhin, bes ätigen verschiedene Mausmodelle eine Schlüsselrolle für T-bet in der Regulation der ILC-Differenzierung und der Entstehung von Lymphknoten. Im Detail konnte gezeigt werden, dass die zusätzliche genetische Ablation von T-bet in ROR tdefizienten Mäusen Differenzierungsentscheidungen in fötalen ILCP zentral beeinflusst. Die Abwesenheit von T-bet in ILCP ermöglichte die Akkumulation von ILCP mit LTi-Aktivität, wodurch die Organogenese von Lymphknoten, unabhängig von ROR t wiederhergestellt wurde. PLZF + ILCP von ROR t/T-bet-Doppeldefizienten Mäusen bestanden bis ins Erwachsenenalter, wo diese Zellen die Darmbarrierefunktionen durch Produktion von IL-22 wiederherstellten. Darüber hinaus erwies sich ROR als entscheidend für die Entwicklung von PLZF + ILCP und die damit verbundene Bildung von Lymphknoten. Insgesamt enthüllen diese Ergebnisse eine neue Rolle für T-bet und ROR in der embryonalen ILC-Differenzierung und der Lymphknoten-Organogenese, und decken die antagonistische Funktion von ROR t innerhalb der differenzierenden ILCP auf, T-bet entgegenzuwirken. Altogether, these data unveil a novel role for T-bet and ROR in embryonic ILC differentiation and LN organogene...

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Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1α is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1α levels are characteristic of the proliferative phenotype and are sensitive to bromodomain and extra-terminal domain (BET) inhibitor treatment. A super-enhancer region highly occupied by the BET family member BRD4 was identified for the PGC-1α gene. BET inhibitor treatment prevented this interaction, leading to a dramatic reduction of PGC-1α expression. Accordingly, BET inhibition diminished respiration and mitochondrial function in cells. In vivo, melanoma models with high PGC-1α expression strongly responded to BET inhibition by reduction of PGC-1α and impaired tumor growth. Altogether, our findings identify epigenetic regulatory elements that define a subset of melanomas with high sensitivity to BET inhibition, which opens up the opportunity to define melanoma patients most likely to respond to this treatment, depending on their tumor characteristics.

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