Hot off the presses! Oct 01 Nat Immunol

The Oct 01 issue of the Nat Immunol is now up on Pubget (About Nat Immunol): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• A long way to go...
  - Nat Immunol 10(10):1035 (2009)
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• Knighting immunology
  - Nat Immunol 10(10):1037 (2009)
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• Renaissance for mouse models of human hematopoiesis and immunobiology
  - Nat Immunol 10(10):1039-1042 (2009)
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• The immune system as an invisible, silent Grand Fugue
  - Nat Immunol 10(10):1043-1045 (2009)
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• The importance of being earnestly selfish
  - Nat Immunol 10(10):1047-1049 (2009)
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• New DNA-sensing pathway feeds RIG-I with RNA
  - Nat Immunol 10(10):1049-1051 (2009)
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• A defining factor for natural killer cell development
  - Nat Immunol 10(10):1051-1052 (2009)
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• Beyond peptidoglycan for Nod2
  - Nat Immunol 10(10):1053-1054 (2009)
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• Research Highlights
  - Nat Immunol 10(10):1055 (2009)
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• The cunning little vixen: Foxo and the cycle of life and death
  - Nat Immunol 10(10):1057-1063 (2009)
  A screen for increased longevity in Caenorhabditis elegans has identified a transcription factor that programs cells for resistance to oxidative stress, DNA repair and cell cycle control. The mammalian orthologs of this factor are referred to as 'Foxo' for 'Forkhead box', with the second 'o' in the name denoting a subfamily of four members related by sequence. This family of factors is regulated by growth factors, oxidative stress or nutrient deprivation. Thus, it might readily control the inflammatory conflagration associated with infection-driven lymphocyte proliferation. Surprisingly, the first insights into Foxo-mediated immune regulation have instead revealed direct control of highly specialized genes of the adaptive immune system.
• RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III–transcribed RNA intermediate
  Ablasser A Bauernfeind F Hartmann G Latz E Fitzgerald KA Hornung V - Nat Immunol 10(10):1065-1072 (2009)
  RNA is sensed by Toll-like receptor 7 (TLR7) and TLR8 or by the RNA helicases LGP2, Mda5 and RIG-I to trigger antiviral responses. Much less is known about sensors for DNA. Here we identify a novel DNA-sensing pathway involving RNA polymerase III and RIG-I. In this pathway, AT-rich double-stranded DNA (dsDNA) served as a template for RNA polymerase III and was transcribed into double-stranded RNA (dsRNA) containing a 5'-triphosphate moiety. Activation of RIG-I by this dsRNA induced production of type I interferon and activation of the transcription factor NF-B. This pathway was important in the sensing of Epstein-Barr virus–encoded small RNAs, which were transcribed by RNA polymerase III and then triggered RIG-I activation. Thus, RNA polymerase III and RIG-I are pivotal in sensing viral DNA.
• Activation of innate immune antiviral responses by Nod2
  - Nat Immunol 10(10):1073-1080 (2009)
  Pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs) and RIG-like helicase (RLH) receptors, are involved in innate immune antiviral responses. Here we show that nucleotide-binding oligomerization domain 2 (Nod2) can also function as a cytoplasmic viral PRR by triggering activation of interferon-regulatory factor 3 (IRF3) and production of interferon- (IFN-). After recognition of a viral ssRNA genome, Nod2 used the adaptor protein MAVS to activate IRF3. Nod2-deficient mice failed to produce interferon efficiently and showed enhanced susceptibility to virus-induced pathogenesis. Thus, the function of Nod2 as a viral PRR highlights the important function of Nod2 in host antiviral defense mechanisms.
• Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori
  - Nat Immunol 10(10):1081-1088 (2009)
  Cooperation between different innate signaling pathways induced by pattern-recognition receptors (PRRs) on dendritic cells (DCs) is crucial for tailoring adaptive immunity to pathogens. Here we show that carbohydrate-specific signaling through the C-type lectin DC-SIGN tailored cytokine production in response to distinct pathogens. DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1. Mannose-expressing Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) induced the recruitment of effector proteins to the DC-SIGN signalosome to activate Raf-1, whereas fucose-expressing pathogens such as Helicobacter pylori actively dissociated the KSR1–CNK–Raf-1 complex from the DC-SIGN signalosome. This dynamic regulation of the signalosome by mannose- and fucose-expressing pathogens led to the enhancement or suppression of proinflammatory responses, respectively. Our stu! dy reveals another level of plasticity in tailoring adaptive immunity to pathogens.
• Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production
  - Nat Immunol 10(10):1089-1095 (2009)
  Toll-like receptors (TLRs) are pivotal in innate immunity and inflammation. Here we show that genetic deficiency in Peli1, an E3 ubiquitin ligase, attenuated the induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and rendered mice resistant to septic shock. Peli1 was required for TLR3-induced activation of IB kinase (IKK) and its 'downstream' target, transcription factor NF-B, but was dispensable for IKK–NF-B activation induced by several other TLRs and the interleukin 1 (IL-1) receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.
• Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation
  - Nat Immunol 10(10):1096-1101 (2009)
  Celiac disease driven by an antigluten T cell response is strongly associated with the histocompatibility antigen HLA-DQ2.5 but is barely associated with HLA-DQ2.2. Yet these molecules have very similar peptide-binding motifs and both present gluten T cell epitopes. We found that DQ2.5+ antigen-presenting cells (APCs) had greater stability of bound peptides and protracted gluten presentation relative to that of DQ2.2+ cells. The improved ability of DQ2.5 to retain its peptide cargo can be ascribed to a polymorphism of DQ22 whereby DQ2.5 (tyrosine) can establish a hydrogen bond to the peptide main chain but DQ2.2 (phenylalanine) cannot. Our findings suggest that the kinetic stability of complexes of peptide and major histocompatibility complex (MHC) is of importance for the association of HLA with disease.
• Transcription elongation factor ELL2 directs immunoglobulin secretion in plasma cells by stimulating altered RNA processing
  - Nat Immunol 10(10):1102-1109 (2009)
  Immunoglobulin secretion is modulated by competition between the use of a weak promoter-proximal poly(A) site and a nonconsensus splice site in the final secretory-specific exon of the heavy chain pre-mRNA. The RNA polymerase II transcription elongation factor ELL2, which is induced in plasma cells, enhanced both polyadenylation and exon skipping with the gene encoding the immunoglobulin heavy-chain complex (Igh) and reporter constructs. Lowering ELL2 expression by transfection of heterogenous ribonucleoprotein F (hnRNP F) or small interfering RNA resulted in lower abundance of secretory-specific forms of immunoglobulin heavy-chain mRNA. ELL2 and the polyadenylation factor CstF-64 tracked together with RNA polymerase II across the Igh- and -gene segments; the association of both factors was blocked by ELL2-specific small interfering RNA. Thus, loading of ELL2 and CstF-64 on RNA polymerase II was linked, caused enhanced use of the proximal poly(A) site and was necessary! for processing of immunoglobulin heavy-chain mRNA.
• Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development
  - Nat Immunol 10(10):1110-1117 (2009)
  Signals through the pre–B cell antigen receptor (pre-BCR) and interleukin 7 receptor (IL-7R) coordinate pre–B cell population expansion with subsequent recombination of the locus encoding immunoglobulin -chain (Igk). Although many 'downstream' effectors of each receptor are known, how they integrate to mediate development has remained unclear. Here we report that pre-BCR-mediated activation of the Ras-MEK-Erk signaling pathway silenced transcription of Ccnd3 (encoding cyclin D3) and coordinated exit from the cell cycle with induction of the transcription factor E2A and the initiation of Igk recombination. IL-7R-mediated activation of the transcription factor STAT5 opposed this pathway by promoting Ccnd3 expression and concomitantly inhibiting Igk transcription by binding to the Igk intronic enhancer and preventing E2A recruitment. Our data show how pre-BCR signaling poises pre–B cells to undergo differentiation after escape from IL-7R signaling.
• The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development
  Gascoyne DM Long E Veiga-Fernandes H de Boer J Williams O Seddon B Coles M Kioussis D Brady HJ - Nat Immunol 10(10):1118-1124 (2009)
  Natural killer (NK) cells are a subset of lymphocytes crucial for innate immunity and modification of adaptive immune responses. In contrast to commitment to the T cell or B cell lineage, little is known about NK cell lineage commitment. Here we show that the basic leucine zipper (bZIP) transcription factor E4BP4 (also called NFIL3) is essential for generation of the NK cell lineage. E4BP4-deficient mice (Nfil3-/–; called 'E4bp4-/–' here) had B cells, T cells and NKT cells but specifically lack NK cells and showed severely impaired NK cell–mediated cytotoxicity. Overexpression of E4bp4 was sufficient to increase NK cell production from hematopoietic progenitor cells. E4BP4 acted in a cell-intrinsic manner 'downstream' of the interleukin 15 receptor (IL-15R) and through the transcription factor Id2. E4bp4-/- mice may provide a model for definitive analysis of the contribution of NK cells to immune responses and pathologies.
• Thymic self-reactivity selects natural interleukin 17–producing T cells that can regulate peripheral inflammation
  - Nat Immunol 10(10):1125-1132 (2009)
  Interleukin 17 (IL-17)-producing CD4+ helper T cells (TH-17 cells) share a developmental relationship with Foxp3+ regulatory T cells (Treg cells). Here we show that a TH-17 population differentiates in the thymus in a manner influenced by recognition of self antigen and by the cytokines IL-6 and transforming growth factor- (TGF-). Like previously described TH-17 cells, the TH-17 cells that developed in the thymus expressed the transcription factor RORt and the IL-23 receptor. These cells also expressed 41 integrins and the chemokine receptor CCR6 and were recruited to the lung, gut and liver. In the liver, these cells secreted IL-22 in response to self antigen and mediated host protection during inflammation. Thus, TH-17 cells, like Treg cells, can be selected by self antigens in the thymus.