IL-7 induces type 2 cytokine response in lung ILC2s and regulates GATA3 and CD25 expression.

Interleukin-7 is a cytokine with well-established roles in lymphocyte development and more recently, an expanded role in immune function. IL-7Rα is highly expressed by innate lymphoid cells (ILCs), but how IL-7 directs the development or function of ILCs is not well studied. Using mice with inducible deletion of IL-7Rα, we showed that loss of IL-7 signaling led to impaired production of IL-5, IL-13 and amphiregulin in lung ST2+ group 2 innate lymphoid cells (ILC2s) following influenza/A infection. Conversely, mice treated with IL-7 increased production of IL-5 and IL-13 by lung ILC2s. Moreover, we showed that IL-7 enhanced GATA3 and CD25 expression in ILC2s and loss of IL-7 signaling led to their reduced expression. Altogether, this study demonstrates that IL-7 regulates the function of ILC2s during airway viral infection and induces GATA3 and CD25 expression.

CCL5 production in lung cancer cells leads to an altered immune microenvironment and promotes tumor development.

Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumor-derived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRASG12V or EGFRL858R expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (Tregs), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high CCL5 expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.

Hyper-Editing of Cell-Cycle Regulatory and Tumor Suppressor RNA Promotes Malignant Progenitor Propagation.

Adenosine deaminase associated with RNA1 (ADAR1) deregulation contributes to therapeutic resistance in many malignancies. Here we show that ADAR1-induced hyper-editing in normal human hematopoietic progenitors impairs miR-26a maturation, which represses CDKN1A expression indirectly via EZH2, thereby accelerating cell-cycle transit. However, in blast crisis chronic myeloid leukemia progenitors, loss of EZH2 expression and increased CDKN1A oppose cell-cycle transit. Moreover, A-to-I editing of both the MDM2 regulatory microRNA and its binding site within the 3' UTR region stabilizes MDM2 transcripts, thereby enhancing blast crisis progenitor propagation. These data reveal a dual mechanism governing malignant transformation of progenitors that is predicated on hyper-editing of cell-cycle-regulatory miRNAs and the 3' UTR binding site of tumor suppressor miRNAs.

Population genetic structure of the Culex pipiens (Diptera: Culicidae) complex, vectors of West Nile virus, in five habitats.

BACKGROUND: The Culex pipiens complex consists of several morphologically similar, closely related species. In the United States, Cx. pipiens L. is distributed North of 39° latitude, while Cx. quinquefasciatus Say occurs South of 36° latitude; a hybrid zone occurs between these two latitudes including in the Central Valley of California. Members of the Cx. pipiens complex and their hybrids are vectors for West Nile virus (WNv). Hybrid offspring of Cx. pipiens and Cx. quinquefasciatus have been found to have enhanced transmission rates of WNv over those of pure populations of each species. We investigated whether hybrids of Cx. pipiens and Cx. quinquefasciatus occurred more frequently in any of five habitats which were dairies, rural, suburban, and urban areas, and wetlands. In addition, the proportion of alleles unique to Cx. quinquefasciatus and Cx. pipiens found in each habitat-associated population were determined. METHODS: Amplified fragment length polymorphism (AFLP) markers were used to compare the population structure of the Cx. pipiens complex from each habitat to geographically distant populations considered pure Cx. pipiens and Cx. quinquefasciatus. Structure analyses were used to assign individuals to either Cx. pipiens, Cx. quinquefasciatus, or hybrids of the Cx. pipiens complex. The ancestry of hybrids (F1, F2, or backcrossed) in relation to the two parent populations was estimated for each Central Valley population. Loci unique to the pure Cx. pipiens population and the pure Cx. quinquefasciatus population were determined. The proportion of loci unique to Cx. pipiens and Cx. quinquefasciatus populations were subsequently determined for each population from the five Merced habitats and from the Oroville California population. The unique loci found in Merced populations and not in Cx. pipiens or Cx. quinquefasciatus were also determined. A principal components analysis was run, as was an analysis to determine loci under putative selection. RESULTS: The Structure Harvester analysis found K = 3, and the Culex pipiens complex mosquitoes formed a genetic cluster distinct from Cx. quinquefasciatus and Cx. pipiens. Individuals collected from each habitat were nearly all hybrids. However, Cx. pipiens complex collected near dairies had more individuals categorized as Cx. pipiens than collections from the other habitats. None of the mosquitoes collected in Merced or Oroville were considered pure Cx. quinquefasciatus. Significant genetic divergence was detected among the Cx. pipiens complex from the five habitats in Merced; Cx. pipiens complex mosquitoes from dairies were divergent from the urban and suburban populations. New Hybrids analysis found that individuals from all five Merced habitat-associated populations and the population from Oroville were primarily categorized as hybrids backcrossed to the Cx. pipiens population. Finally, all five habitat-associated populations shared more alleles with Cx. pipiens than with Cx. quinquefasciatus, even though the pure Cx. quinquefasciatus population was more geographically proximate to Merced. Results from the principal component analysis, and the occurrence of several unique loci in Merced populations, suggest that Cx. pipiens molestus may also occur in the habitats sampled. CONCLUSIONS: Nearly all mosquitoes in the five habitats in Merced in the Central Valley of California area were hybrids of Cx. pipiens and Cx. quinquefasciatus, consisting of hybrids backcrossed to Cx. pipiens. Habitat-associated mosquitoes collected near dairies had more individuals consisting of pure Cx. pipiens, and no mosquitoes from Merced or Oroville CA classified as pure Cx. quinquefasciatus. The genetic distances among Cx. pipiens and Cx. quinquefasciatus, and hybrid populations agree with previous studies using other molecular markers. Cx. pipiens hybrids in Merced shared more alleles with Cx. pipiens than Cx. quinquefasciatus which was unexpected, since Merced is geographically closer to the northern limit of Cx. quinquefasciatus distribution. Culex pipiens molestus may occur in more habitats in the Central Valley than previously suspected, which warrants further investigation. Future studies could investigate the vector competence of hybrids backcrossed to either Cx. pipiens or Cx. quinquefasciatus parent for their ability to transmit West Nile virus.

RNA rewriting, recoding, and rewiring in human disease.

ADAR (adenosine deAminase acting on RNA) editases catalyze the deamination of adenosine to inosine (A-to-I), a post-transcriptional modification that alters coding and non-coding RNA stability and function. ADAR editases such as ADAR1 have recently been shown to play a key role in normal stem cell maintenance. While ADAR mutations are associated with hereditary autoimmune diseases such as Aicardi-Goutières syndrome, ADAR copy-number alterations and editase activation have been associated with progression of a broad array of malignancies. In this review we discuss evidence linking aberrant A-to-I editing to cancer and other degenerative diseases, and the mechanisms that may be targeted by novel therapeutic strategies.