Rockefeller University

About: Rockefeller University is a education organization based out in New York, New York, United States. It is known for research contribution in the topics: Population & Gene. The organization has 15867 authors who have published 32938 publications receiving 2940261 citations. The organization is also known as: Rockefeller University & Rockefeller Institute.

Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity

Abstract: The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.

Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.

Abstract: Psoriasis vulgaris is a common chronic inflammatory skin disease characterized by hyperproliferative epidermis and mixed cutaneous lymphocytic infiltrate. While initially regarded as a primary disease of keratinocyte differentiation, effective immune-modulating therapies demonstrate the vital role played by the immune system in psoriatic disease pathogenesis.1–4 The T cells involved in lesion formation were initially thought to be Th1 differentiated based on interferon (IFN)-γ and interleukin (IL)-2 production.5–7 However, the recent discovery of the Th17 T-helper cell subset, and its potential involvement in psoriasis, generates even more complexity to this disease. Th17 cells have recently been classified as distinct from Th1 and Th2 subsets.8,9 They are defined by the ability to synthesize IL-17 in response to antigen-presenting cell-derived IL-23 and other differentiating cytokines.10–13 In addition, Th17 cells have been reported to cosynthesize IL-17 and IFN-γ14 as well as IL-22.15,16 Indeed, in murine systems, IL-22 production occurs overwhelmingly within the Th17 subset.15 Psoriatic skin lesions are reported to have increased gene expression of IL-23,17 IL-17 and IL-22,18–21 prompting investigators to probe deeper into the potential involvement of Th17 cells in psoriasis. While models of epidermal hyperproliferation have focused on IL-22 as being central to psoriasis pathogenesis via induction of keratinocyte proliferation and acanthosis,22–24 both IL-22 and IL-17 have been shown to induce keratinocyte gene expression of antimicrobials β-defensin 2, β-defensin 3, S100A8 and S100A9, all upregulated in psoriatic lesions.15,22,25 Besides the increased expression of antimicrobial genes, however, the contribution of IL-17 to psoriasis pathogenesis has not been thoroughly investigated. This is in contrast to IL-17 being extensively implicated in chemokine-induced neutrophil recruitment in asthma, chronic obstructive pulmonary disease and cystic fibrosis.26–28 The chemokines that are considered to be neutrophil chemoattractants belong to the ELR+ CXC subfamily, named by the presence of a Glu-Leu-Arg motif at residues 4–6.29,30 Members of this subfamily include CXCL1–8, except CXCL4.29 Indeed, IL-17 has previously been shown to induce the production of CXCL1 and CXCL8 in bronchial epithelial cells,27,28 fibroblasts31 and keratinocytes,32 and neutralizing antibodies to IL-17 or its receptor can block this induction.28,32 Even with increasing evidence for the involvement of Th17 cells in psoriasis pathogenesis, the relative effects of the Th17 cytokines IL-17 and IL-22 and the Th1 cytokine IFN-γ on the skin are unknown. In this study, we sought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors.

Developmental regulation of MHC class II transport in mouse dendritic cells

Abstract: Dendritic cells (DCs) have the unique capacity to initiate primary and secondary immune responses. They acquire antigens in peripheral tissues and migrate to lymphoid organs where they present processed peptides to T cells. DCs must therefore exist in distinct functional states, an idea that is supported by observations that they downregulate endocytosis and upregulate surface molecules of the class II major histocompatibility complex (MHC) upon maturation. Here we investigate the features of DC maturation by reconstituting the terminal differentiation of mouse DCs in vitro and in situ. We find that early DCs, corresponding to those found in peripheral tissues, exhibit a phenotype in which most class II molecules are intracellular and localized to lysosomes. Upon maturation, these cells give rise to a new intermediate phenotype in which intracellular class II molecules are found in peripheral non-lysosomal vesicles, similar to the specialized CIIV population seen in B cells. The intermediate cells then differentiate into late DCs which express almost all of their class II molecules on the plasma membrane. These variations in class II compartmentalization are accompanied by dramatic alterations in the intracellular transport of the new class II molecules and in antigen presentation. We found that although early DCs could not present antigen immediately after uptake, efficient presentation of the previously internalized antigen occurred after maturation, 24-48 hours later. By regulating class II transport and compartmentalization, DCs are able to delay antigen display, a property crucial to their role in immune surveillance.

The Chromosomal Passenger Complex (CPC): From Easy Rider to the Godfather of Mitosis

Abstract: Successful cell division requires the precise and timely coordination of chromosomal, cytoskeletal and membrane trafficking events. These processes are regulated by the competing actions of protein kinases and phosphatases. Aurora B is one of the most intensively studied kinases. In conjunction with inner centromere protein (INCENP), borealin (also known as Dasra) and survivin it forms the chromosomal passenger complex (CPC). This complex targets to different locations at differing times during mitosis, where it regulates key mitotic events: correction of chromosome-microtubule attachment errors; activation of the spindle assembly checkpoint; and construction and regulation of the contractile apparatus that drives cytokinesis. Our growing understanding of the CPC has seen it develop from a mere passenger riding on the chromosomes to one of the main controllers of mitosis.