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)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Knighting immunology
  - Nat Immunol 10(10):1037 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Renaissance for mouse models of human hematopoiesis and immunobiology
  - Nat Immunol 10(10):1039-1042 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• The immune system as an invisible, silent Grand Fugue
  - Nat Immunol 10(10):1043-1045 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• The importance of being earnestly selfish
  - Nat Immunol 10(10):1047-1049 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• New DNA-sensing pathway feeds RIG-I with RNA
  - Nat Immunol 10(10):1049-1051 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• A defining factor for natural killer cell development
  - Nat Immunol 10(10):1051-1052 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Beyond peptidoglycan for Nod2
  - Nat Immunol 10(10):1053-1054 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Research Highlights
  - Nat Immunol 10(10):1055 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• 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.

Hot off the presses! Aug 01 Nat Immunol

The Aug 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:

• Hyping research
  - Nat Immunol 10(8):795 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Jean Dausset 1916–2009
  - Nat Immunol 10(8):797 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• RNAi screening: tips and techniques
  - Nat Immunol 10(8):799-804 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Themis imposes new law and order on positive selection
  - Nat Immunol 10(8):805-806 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• TH2 bias: Mina tips the balance
  - Nat Immunol 10(8):806-808 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• New insight into the everlasting host-pathogen arms race
  - Nat Immunol 10(8):808-809 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Dead man walking: how thymocytes scan the medulla
  - Nat Immunol 10(8):809-811 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• One problem, two solutions
  - Nat Immunol 10(8):811-813 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Research Highlights
  - Nat Immunol 10(8):815 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• RAG: a recombinase diversified
  - Nat Immunol 10(8):817-821 (2009)
  During B cell and T cell development, the lymphoid-specific proteins RAG-1 and RAG-2 act together to initiate the assembly of antigen receptor genes through a series of site-specific somatic DNA rearrangements that are collectively called variable-diversity-joining (V(D)J) recombination. In the past 20 years, a great deal has been learned about the enzymatic activities of the RAG-1–RAG-2 complex. Recent studies have identified several new and exciting regulatory functions of the RAG-1–RAG-2 complex. Here we discuss some of these functions and suggest that the RAG-1–RAG-2 complex nucleates a specialized subnuclear compartment that we call the 'V(D)J recombination factory'.
• The impact of negative selection on thymocyte migration in the medulla
  - Nat Immunol 10(8):823-830 (2009)
  Developing thymocytes are screened for self-reactivity before they exit the thymus, but how thymocytes scan the medulla for self antigens is unclear. Using two-photon microscopy, we observed that medullary thymocytes migrated rapidly and made frequent, transient contacts with dendritic cells. In the presence of a negative selecting ligand, thymocytes slowed, became confined to areas of approximately 30 m in diameter and had increased contact with dendritic cells surrounding confinement zones. One third of polyclonal medullary thymocytes also showed confined, slower migration and may correspond to autoreactive thymocytes. Our data suggest that many autoreactive thymocytes do not undergo immediate arrest and death after encountering a negative selecting ligand but instead adopt an altered migration program while remaining in the medullary microenvironment.
• Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection
  - Nat Immunol 10(8):831-839 (2009)
  T cell antigen receptor (TCR) signaling in CD4+CD8+ double-positive thymocytes determines cell survival and lineage commitment, but the genetic and molecular basis of this process is poorly defined. To address this issue, we used ethylnitrosourea mutagenesis to identify a previously unknown T lineage–specific gene, Themis, which is critical for the completion of positive selection. Themis contains a tandem repeat of a unique globular domain (called 'CABIT' here) that includes a cysteine motif that defines a family of five uncharacterized vertebrate proteins with orthologs in most animal species. Themis-deficient thymocytes showed no substantial impairment in early TCR signaling but did show altered expression of genes involved in the cell cycle and survival before and during positive selection. Our data suggest a unique function for Themis in sustaining positive selection.
• Themis, a T cell–specific protein important for late thymocyte development
  - Nat Immunol 10(8):840-847 (2009)
  During positive selection, thymocytes transition through a stage during which T cell antigen receptor (TCR) signaling controls CD4-versus-CD8 lineage 'choice' and subsequent maturation. Here we describe a previously unknown T cell–specific protein, Themis, that serves a distinct function during this stage. In Themis-/- mice, thymocyte selection was impaired and the number of transitional CD4+CD8int thymocytes as well as CD4+ or CD8+ single-positive thymocytes was lower. Notably, although we detected no overt TCR-proximal signaling deficiencies, Themis-/- CD4+CD8int thymocytes showed developmental defects consistent with attenuated signaling that were reversible by TCR stimulation. Our results identify Themis as a critical component of the T cell developmental program and suggest that Themis functions to sustain and/or integrate signals required for proper lineage commitment and maturation.
• Themis controls thymocyte selection through regulation of T cell antigen receptor–mediated signaling
  - Nat Immunol 10(8):848-856 (2009)
  Themis (thymocyte-expressed molecule involved in selection), a member of a family of proteins with unknown functions, is highly conserved among vertebrates. Here we found that Themis had high expression in thymocytes between the pre–T cell antigen receptor (pre-TCR) and positive-selection checkpoints and low expression in mature T cells. Themis-deficient thymocytes showed defective positive selection, which resulted in fewer mature thymocytes. Negative selection was also impaired in Themis-deficient mice. A greater percentage of Themis-deficient T cells had CD4+CD25+Foxp3+ regulatory and CD62LloCD44hi memory phenotypes than did wild-type T cells. In support of the idea that Themis is involved in TCR signaling, this protein was phosphorylated quickly after TCR stimulation and was needed for optimal TCR-driven calcium mobilization and activation of the kinase Erk.
• Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells
  - Nat Immunol 10(8):857-863 (2009)
  Interleukin 22 (IL-22) is a cytokine produced by the TH-17 lineage of helper T cells and NK-22 subset of natural killer cells that acts on epithelial cells and keratinocytes and has been linked to skin homeostasis and inflammation. Here we characterize a population of human skin-homing memory CD4+ T cells that expressed the chemokine receptors CCR10, CCR6 and CCR4 and produced IL-22 but neither IL-17 nor interferon- (IFN-). Clones isolated from this population produced IL-22 only and had low or undetectable expression of the TH-17 and T helper type 1 (TH1) transcription factors RORt and T-bet. The differentiation of T cells producing only IL-22 was efficiently induced in naive T cells by plasmacytoid dendritic cells in an IL-6- and tumor necrosis factor–dependent way. Our findings delineate a previously unknown subset of human CD4+ effector T cells dedicated to skin pathophysiology.
• Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells
  - Nat Immunol 10(8):864-871 (2009)
  Interleukin 22 (IL-22) is a member of the IL-10 cytokine family that is involved in inflammatory and wound healing processes. Originally considered a T helper type 1 (TH1)-associated cytokine, IL-22 has since been shown to be produced mainly by IL-17-producing helper T cells (TH-17 cells). Here we describe a previously uncharacterized IL-22-producing human helper T cell population that coexpressed the chemokine receptor CCR6 and the skin-homing receptors CCR4 and CCR10. These cells were distinct from both TH-17 cells and TH1 cells. Downregulation of either the aryl hydrocarbon receptor (AHR) or the transcription factor RORC by RNA-mediated interference affected IL-22 production, whereas IL-17 production was affected only by downregulation of RORC by RNA-mediated interference. AHR agonists substantially altered the balance of IL-22- versus IL-17-producing cells. This subset of IL-22-producing cells may be important in skin homeostasis and pathology.
• Mina, an Il4 repressor, controls T helper type 2 bias
  - Nat Immunol 10(8):872-879 (2009)
  T helper type 2 (TH2) bias, which is the propensity of naive CD4+ T cells to differentiate into interleukin 4 (IL-4)-secreting TH2 cells, is a genetic trait that affects susceptibility to infectious, autoimmune and allergic diseases. TH2 bias correlates with the amount of IL-4 initially secreted by newly activated helper T cells that feeds back positively through the pathway of the IL-4 receptor and the transcription factors STAT6 and GATA-3 to drive TH2 development. Here we identify Mina, a member of the jumonji C (JmjC) protein family, as a genetic determinant of TH2 bias. Mina specifically bound to and repressed the Il4 promoter. Mina overexpression in transgenic mice impaired Il4 expression, whereas its knockdown in primary CD4+ T cells led to Il4 derepression. Our findings collectively provide mechanistic insight into an Il4-regulatory pathway that controls helper T cell differentiation and genetic variation in TH2 bias.
• Essential function for the GTPase TC21 in homeostatic antigen receptor signaling
  - Nat Immunol 10(8):880-888 (2009)
  T cell antigen receptors (TCRs) and B cell antigen receptors (BCRs) transmit low-grade signals necessary for the survival and maintenance of mature cell pools. We show here that TC21, a small GTPase encoded by Rras2, interacted constitutively with both kinds of receptors. Expression of a dominant negative TC21 mutant in T cells produced a rapid decrease in cell viability, and Rras2-/- mice were lymphopenic, possibly as a result of diminished homeostatic proliferation and impaired T cell and B cell survival. In contrast, TC21 was overexpressed in several human lymphoid malignancies. Finally, the p110 catalytic subunit of phosphatidylinositol-3-OH kinase (PI(3)K) was recruited to the TCR and BCR in a TC21-dependent way. Consequently, we propose TC21 directly links antigen receptors to PI(3)K-mediated survival pathways.
• Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell–stimulating programs in basophils
  - Nat Immunol 10(8):889-898 (2009)
  Immunoglobulin D (IgD) is an enigmatic antibody isotype that mature B cells express together with IgM through alternative RNA splicing. Here we report active T cell–dependent and T cell–independent IgM-to-IgD class switching in B cells of the human upper respiratory mucosa. This process required activation-induced cytidine deaminase (AID) and generated local and circulating IgD-producing plasmablasts reactive to respiratory bacteria. Circulating IgD bound to basophils through a calcium-mobilizing receptor that induced antimicrobial, opsonizing, inflammatory and B cell–stimulating factors, including cathelicidin, interleukin 1 (IL-1), IL-4 and B cell–activating factor (BAFF), after IgD crosslinking. By showing dysregulation of IgD class–switched B cells and 'IgD-armed' basophils in autoinflammatory syndromes with periodic fever, our data indicate that IgD orchestrates an ancestral surveillance system at the interface between immunity and inflammation.
• Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair
  - Nat Immunol 10(8):899-906 (2009)
  Induction of macrophage necrosis is a strategy used by virulent Mycobacterium tuberculosis (Mtb) to avoid innate host defense. In contrast, attenuated Mtb causes apoptosis, which limits bacterial replication and promotes T cell cross-priming by antigen-presenting cells. Here we show that Mtb infection causes plasma membrane microdisruptions. Resealing of these lesions, a process crucial for preventing necrosis and promoting apoptosis, required translocation of lysosomal and Golgi apparatus–derived vesicles to the plasma membrane. Plasma membrane repair depended on prostaglandin E2 (PGE2), which regulates synaptotagmin 7 (Syt-7), the calcium sensor involved in the lysosome-mediated repair mechanism. By inducing production of lipoxin A4 (LXA4), which blocks PGE2 biosynthesis, virulent Mtb prevented membrane repair and induced necrosis. Thus, virulent Mtb impairs macrophage plasma membrane repair to evade host defenses.
• Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P2 and PtdIns(3,4,5)P3 promotes immunity to mycobacteria
  - Nat Immunol 10(8):907-917 (2009)
  Vertebrate immunity to infection enlists a newly identified family of 47-kilodalton immunity-related GTPases (IRGs). One IRG in particular, Irgm1, is essential for macrophage host defense against phagosomal pathogens, including Mycobacterium tuberculosis (Mtb). Here we show that Irgm1 targets the mycobacterial phagosome through lipid-mediated interactions with phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2) and PtdIns(3,4,5)P3. An isolated Irgm1 amphipathic helix conferred lipid binding in vitro and in vivo. Substitutions in this region blocked phagosome recruitment and failed to complement the antimicrobial defect in Irgm1-/- macrophages. Removal of PtdIns(3,4,5)P3 or inhibition of class I phosphatidylinositol-3-OH kinase (PI(3)K) mimicked this effect in wild-type cells. Cooperation between Irgm1 and PI(3)K further facilitated the engagement of Irgm1 with its fusogenic effectors at the site of infection, thereby ensuring pathogen-directed responses during innate! immunity.
• A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis–induced macrophage apoptosis
  - Nat Immunol 10(8):918-926 (2009)
  Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosis of infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spread of mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediated macrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led to phosphorylation of FLIPS, which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIPS, which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis–triggered macrophage cell death.

Hot off the presses! Jul 01 Nat Immunol

The Jul 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:

• Biotech bailout?
  - Nat Immunol 10(7):667 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• NKT cells turn ten
  - Nat Immunol 10(7):669-671 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• NIAID workshop on immunity to malaria: addressing immunological challenges
  - Nat Immunol 10(7):673-678 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Basophils trump dendritic cells as APCs for TH2 responses
  - Nat Immunol 10(7):679-681 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• CSF-1R, DAP12 and beta-catenin: a ménage à trois
  - Nat Immunol 10(7):681-683 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• ASMase: the tailor of cytotoxic T cell granule exocytosis
  - Nat Immunol 10(7):683-685 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• A novel modifier of regulatory T cells
  - Nat Immunol 10(7):685-686 (2009)
  I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Research Highlights
  - Nat Immunol 10(7):687 (2009)
  I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Immunology Select this option to purchase a personal subscription to Nature Immunology.
• Foxp3+ regulatory T cells: differentiation, specification, subphenotypes
  - Nat Immunol 10(7):689-695 (2009)
  Regulatory T cells (Treg cells) characterized by expression of the transcription factor Foxp3 play a key role in immune homeostasis. Rather than a monomorphic population strictly determined by Foxp3 as a 'master regulator', the emerging view is one of Treg cells as a population with many levels of complexity. Several regulatory factors partake in the control of their transcriptional 'signature', with Foxp3 being a key regulator but insufficient and unnecessary to specify all aspects of the lineage. Distinct subphenotypes of Foxp3+ Treg cells are found in different anatomical locations. Some subphenotypes specifically control different facets of effector T cell function and, perhaps surprisingly, share transcriptional control elements with the very cells they regulate. This review will focus on these novel aspects of Treg cell diversity.
• MHC class II–dependent basophil–CD4+ T cell interactions promote TH2 cytokine–dependent immunity
  - Nat Immunol 10(7):697-705 (2009)
  Dendritic cells can prime naive CD4+ T cells; however, here we demonstrate that dendritic cell–mediated priming was insufficient for the development of T helper type 2 cell–dependent immunity. We identify basophils as a dominant cell population that coexpressed major histocompatibility complex class II and interleukin 4 message after helminth infection. Basophilia was promoted by thymic stromal lymphopoietin, and depletion of basophils impaired immunity to helminth infection. Basophils promoted antigen-specific CD4+ T cell proliferation and interleukin 4 production in vitro, and transfer of basophils augmented the population expansion of helminth-responsive CD4+ T cells in vivo. Collectively, our studies suggest that major histocompatibility complex class II–dependent interactions between basophils and CD4+ T cells promote T helper type 2 cytokine responses and immunity to helminth infection.
• Basophils contribute to TH2-IgE responses in vivo via IL-4 production and presentation of peptide–MHC class II complexes to CD4+ T cells
  - Nat Immunol 10(7):706-712 (2009)
  Basophils express major histocompatibility complex class II, CD80 and CD86 and produce interleukin 4 (IL-4) in various conditions. Here we show that when incubated with IL-3 and antigen or complexes of antigen and immunoglobulin E (IgE), basophils internalized, processed and presented antigen as complexes of peptide and major histocompatibility complex class II and produced IL-4. Intravenous administration of ovalbumin-pulsed basophils into naive mice 'preferentially' induced the development of naive ovalbumin-specific CD4+ T cells into T helper type 2 (TH2) cells. Mice immunized in this way, when challenged by intravenous administration of ovalbumin, promptly produced ovalbumin-specific IgG1 and IgE. Finally, intravenous administration of IgE complexes rapidly induced TH2 cells only in the presence of endogenous basophils, which suggests that basophils are potent antigen-presenting cells that 'preferentially' augment TH2-IgE responses by capturing IgE complex.
• Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response
  - Nat Immunol 10(7):713-720 (2009)
  T helper type 2 (TH2)-mediated immune responses are induced after infection with multicellular parasites and can be triggered by a variety of allergens. The mechanisms of induction and the antigen-presenting cells involved in the activation of TH2 responses remain poorly defined, and the innate immune sensing pathways activated by parasites and allergens are largely unknown. Basophils are required for the in vivo induction of TH2 responses by protease allergens. Here we show that basophils also function as antigen-presenting cells. We show that although dendritic cells were dispensable for allergen-induced activation of TH2 responses in vitro and in vivo, antigen presentation by basophils was necessary and sufficient for this. Thus, basophils function as antigen-presenting cells for TH2 differentiation in response to protease allergens.
• Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor
  - Nat Immunol 10(7):721-727 (2009)
  Activation of the complement system generates potent chemoattractants and leads to the opsonization of cells for immune clearance. Short-lived protease complexes cleave complement component C3 into anaphylatoxin C3a and opsonin C3b. Here we report the crystal structure of the C3 convertase formed by C3b and the protease fragment Bb, which was stabilized by the bacterial immune-evasion protein SCIN. The data suggest that the proteolytic specificity and activity depend on the formation of dimers of C3 with C3b of the convertase. SCIN blocked the formation of a productive enzyme-substrate complex. Irreversible dissociation of the complex of C3b and Bb is crucial to complement regulation and was determined by slow binding kinetics of the Mg2+-adhesion site in Bb. Understanding the mechanistic basis of the central complement-activation step and microbial immune evasion strategies targeting this step will aid in the development of complement therapeutics.
• Structure of complement fragment C3b–factor H and implications for host protection by complement regulators
  - Nat Immunol 10(7):728-733 (2009)
  Factor H (FH) is an abundant regulator of complement activation and protects host cells from self-attack by complement. Here we provide insight into the regulatory activity of FH by solving the crystal structure of the first four domains of FH in complex with its target, complement fragment C3b. FH interacted with multiple domains of C3b, covering a large, extended surface area. The structure indicated that FH destabilizes the C3 convertase by competition and electrostatic repulsion and that FH enables proteolytic degradation of C3b by providing a binding platform for protease factor I while stabilizing the overall domain arrangement of C3b. Our results offer general models for complement regulation and provide structural explanations for disease-related mutations in the genes encoding both FH and C3b.
• Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin
  - Nat Immunol 10(7):734-743 (2009)
  Macrophage colony-stimulating factor (M-CSF) influences the proliferation and survival of mononuclear phagocytes through the receptor CSF-1R. The adaptor protein DAP12 is critical for the function of mononuclear phagocytes. DAP12-mutant mice and humans have defects in osteoclasts and microglia, as well as brain and bone abnormalities. Here we show DAP12 deficiency impaired the M-CSF-induced proliferation and survival of macrophages in vitro. DAP12-deficient mice had fewer microglia in defined central nervous system areas, and DAP12-deficient progenitors regenerated myeloid cells inefficiently after bone marrow transplantation. Signaling by M-CSF through CSF-1R induced the stabilization and nuclear translocation of beta-catenin, which activated genes involved in the cell cycle. DAP12 was essential for phosphorylation and nuclear accumulation of beta-catenin. Our results provide a mechanistic explanation for the many defects of DAP12-deficient mononuclear phagocytes.
• The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon
  - Nat Immunol 10(7):744-752 (2009)
  E3 ubiquitin ligases are important in both innate and adaptive immunity. Here we report that Nrdp1, an E3 ubiquitin ligase, inhibited the production of proinflammatory cytokines but increased interferon-beta production in Toll-like receptor–triggered macrophages by suppressing adaptor MyD88–dependent activation of transcription factors NF-kappaB and AP-1 while promoting activation of the kinase TBK1 and transcription factor IRF3. Nrdp1 directly bound and polyubiquitinated MyD88 and TBK1, which led to degradation of MyD88 and activation of TBK1. Knockdown of Nrdp1 inhibited the degradation of MyD88 and the activation of TBK1 and IRF3. Nrdp1-transgenic mice showed resistance to lipopolysaccharide-induced endotoxin shock and to infection with vesicular stomatitis virus. Our data suggest that Nrdp1 functions as both an adaptor protein and an E3 unbiquitin ligase to regulate TLR responses in different ways.
• Immunological synapse formation inhibits, via NF-kappaB and FOXO1, the apoptosis of dendritic cells
  - Nat Immunol 10(7):753-760 (2009)
  The immunological synapse (IS) is a cell–cell junction formed between CD4+ T cells and dendritic cells (DCs). Here we show in vitro and in vivo that IS formation inhibits apoptosis of DCs. Consistent with these results, IS formation induced antiapoptotic signaling events, including activation of the kinase Akt1 and localization of the prosurvival transcription factor NF-kappaB and the proapoptotic transcription factor FOXO1 to the nucleus and cytoplasm, respectively. Inhibition of phosphatidylinositol 3-OH kinase and Akt1 partially prevented the antiapoptotic effects of IS formation. Direct stimulation of the IS component CD40 on DCs leads to the activation of Akt1, suggesting the involvement of this receptor in the antiapoptotic effects observed upon IS formation.
• Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes
  - Nat Immunol 10(7):761-768 (2009)
  Granule-mediated cytotoxicity is the main effector mechanism of cytotoxic CD8+ T cells. We report that CD8+ T cells from acid sphingomyelinase (ASMase)-deficient (ASMase-KO) mice are defective in exocytosis of cytolytic effector molecules; this defect resulted in attenuated cytotoxic activity of ASMase-KO CD8+ T cells and delayed elimination of lymphocytic choriomeningitis virus from ASMase-KO mice. Cytolytic granules of ASMase-KO and wild-type CD8+ T cells were equally loaded with granzymes and perforin, and correctly directed to the immunological synapse. In wild-type CD8+ T cells, secretory granules underwent shrinkage by 82% after fusion with the plasma membrane. In ASMase-KO CD8+ T cells, the contraction of secretory granules was markedly impaired. Thus, ASMase is required for contraction of secretory granules and expulsion of cytotoxic effector molecules.
• The receptor S1P1 overrides regulatory T cell–mediated immune suppression through Akt-mTOR
  - Nat Immunol 10(7):769-777 (2009)
  Regulatory T cells (Treg cells) are critically involved in maintaining immunological tolerance, but this potent suppression must be 'quenched' to allow the generation of adaptive immune responses. Here we report that sphingosine 1-phosphate (S1P) receptor type 1 (S1P1) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of Treg cells. Combining loss- and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic Treg precursors and function of mature Treg cells and affected Treg cell–mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of Treg cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing Treg cell–mediated immune suppression, the lipid-activated S1P1-Akt-mTOR pathway orchestrates adaptive immune responses.
• Interleukin 17 acts in synergy with B cell–activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus
  - Nat Immunol 10(7):778-785 (2009)
  Studies have suggested involvement of interleukin 17 (IL-17) in autoimmune diseases, although its effect on B cell biology has not been clearly established. Here we demonstrate that IL-17 alone or in combination with B cell–activating factor controlled the survival and proliferation of human B cells and their differentiation into immunoglobulin-secreting cells. This effect was mediated mainly through the nuclear factor-kappaB-regulated transcription factor Twist-1. In support of the relevance of our observations and the potential involvement of IL-17 in B cell biology, we found that the serum of patients with systemic lupus erythematosus had higher concentrations of IL-17 than did the serum of healthy people and that IL-17 abundance correlated with the disease severity of systemic lupus erythematosus.
• Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation
  - Nat Immunol 10(7):786-793 (2009)
  Subcapsular sinus (SCS) macrophages capture antigens from lymph and present them intact for B cell encounter and follicular delivery. However, the properties of SCS macrophages are poorly defined. Here we show SCS macrophage development depended on lymphotoxin-alpha1beta2, and the cells had low lysosomal enzyme expression and retained opsonized antigens on their surface. Intravital imaging revealed immune complexes moving along macrophage processes into the follicle. Moreover, noncognate B cells relayed antigen opsonized by newly produced antibodies from the subcapsular region to the germinal center, and affinity maturation was impaired when this transport process was disrupted. Thus, we characterize SCS macrophages as specialized antigen-presenting cells functioning at the apex of an antigen transport chain that promotes humoral immunity.

Hot off the presses! Jan 01

The Jan 01 issue of the is now up on Pubget (About ): 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:

• Lighting the way forward
  - Nature Immunology 11(1):1 (2010)
  Although recent progress has aided our understanding of the processes that prevent immune tolerance breakdown, this Focus issue illustrates how much remains unknown about susceptibility to and pathogenesis of autoimmune diseases.
• Levees of immunological tolerance
  - Nature Immunology 11(1):3-6 (2010)
  Immunological tolerance guards against spurious immune responses to body constituents. Tolerance encompasses a network of mechanisms: central and peripheral, cell-autonomous and cell-interactive. Our understanding of these mechanisms has improved greatly over recent years, often reflecting new insights into the processes underlying particular autoimmune diseases. Yet it is possible that important tolerance mechanisms remain to be discovered, perhaps an explanation for the so-far disappointing clinical translation to the prevention and cure of autoimmune diseases.
• Regulatory T cells exert checks and balances on self tolerance and autoimmunity
  - Nature Immunology 11(1):7-13 (2010)
  Immunological self tolerance is maintained at least in part by regulatory T (Treg) cells that actively and dominantly control potentially hazardous self-reactive T cells in the periphery. Antigens that stimulate self-reactive T cells may also activate natural Treg cells, thereby maintaining dominant self tolerance. Conversely, genetic anomalies or environmental agents that specifically or predominantly affect Treg cells cause or predispose to autoimmunity. With recent advances in our understanding of Treg cell development in the thymus and periphery and the molecular mechanism of Treg cell–mediated suppression, new ways of treating immunological diseases by targeting Treg cells at the cellular and molecular levels are envisaged.
• Checkpoints in lymphocyte development and autoimmune disease
  - Nature Immunology 11(1):14-20 (2010)
  Antigen receptor–controlled checkpoints in B lymphocyte development are crucial for the prevention of autoimmune diseases such as systemic lupus erythematosus. Checkpoints at the stage of pre–B cell receptor (pre-BCR) and BCR expression can eliminate certain autoreactive BCRs either by deletion of or anergy induction in cells expressing autoreactive BCRs or by receptor editing. For T cells, the picture is more complex because there are regulatory T (Treg) cells that mediate dominant tolerance, which differs from the recessive tolerance mediated by deletion and anergy. Negative selection of thymocytes may be as essential as Treg cell generation in preventing autoimmune diseases such as type 1 diabetes, but supporting evidence is scarce. Here we discuss several scenarios in which failures at developmental checkpoints result in autoimmunity.
• Mechanisms maintaining peripheral tolerance
  - Nature Immunology 11(1):21-27 (2010)
  The presentation of self-peptide–MHC complexes in the periphery to potentially autoreactive T cells that have escaped negative selection in the thymus poses an important problem to the immune system. In this review, I discuss data that reveal barriers preventing peripheral T cell recognition of self-peptide–MHC complexes, as well as the physiological mechanisms that ensure the elimination or functional inactivation (anergy) of T cells that do come to recognize self-peptide–MHC and threaten the health of the individual.
• Influence of microbial environment on autoimmunity
  - Nature Immunology 11(1):28-35 (2010)
  During protective immune responses, the adaptive arm of the immune system requires activation by signals provided by innate immunity and driven by microbial stimuli. Whether the same rules apply to autoimmune diseases involving clonal self-reactive T and B lymphocytes—a process referred to here as 'adaptive autoimmunity'—is not quite clear. Nevertheless, in these diseases, the innate–adaptive connection is likely to be influenced by the microbial environment. This review integrates the results of experiments analyzing autoimmunity in sterile versus nonsterile conditions and experiments testing the role of innate immune receptor signaling in autoimmunity. It proposes that autoimmune diseases can be divided into two groups, the pathogenesis of which either follows the rules of innate–adaptive connection or does not.
• Autoimmunity: increasing suspects in the CD4+ T cell lineup
  - Nature Immunology 11(1):36-40 (2010)
  Chronic reactivity of CD4+ T cells to autoantigens and to components of the commensal flora drive destructive inflammation in a variety of mouse models of autoimmunity. Insight gained using these models is empowering translational research into human disease. Immunologists are trying to assign disease culpability to one of the ever-growing number of T helper (TH) cell subsets. Although recent discovery of the interleukin 17–producing TH-17 lineage appeared to supplant the pre-eminence of TH1 cells in promoting autoimmunity, the newest data defy simple paradigms. Here we speculate on the respective contributions to autoimmunity made by an increasingly complex list of TH subsets and argue that the TH1 phenotype may be staging a comeback.
• Mixed results with modulation of TH-17 cells in human autoimmune diseases
  - Nature Immunology 11(1):41-44 (2010)
  The outcomes of clinical trials provide the most convincing data to clarify the role of particular cytokines in the pathogenesis of human diseases. The immunology community, for a variety of practical reasons, spends most of its research time and funds on studies in model systems, mainly mice. In this perspective I discuss results of clinical trials assessing the effect of blocking the differentiation and/or function of interleukin-17–producing CD4+ T cells on human autoimmune disease, and devote more limited attention to corroborating preclinical studies from animal models. Thus far, these outcomes in human trials have been mixed, with notable success in psoriasis and Crohn's disease but a negative result in relapsing-remitting multiple sclerosis.
• Research Highlights
  - Nature Immunology 11(1):45 (2010)
  
• Glimpsing the real CD4+ T cell response
  - Nature Immunology 11(1):47-49 (2010)
  The present views of how CD4+ T cells respond to antigen are based largely on artificial systems. A highly sensitive approach that allows normal T cell responses to be monitored in physiological conditions overturns some existing ideas about the differentiation of CD4+ T cells.
• Defensins keep the peace too
  - Nature Immunology 11(1):49-50 (2010)
  The mammalian intestine contains a large number of commensal bacterial strains. New work suggests that antimicrobial peptides used for defense against pathogenic bacteria are also used to adjust the balance among bacterial populations and to control intestinal homeostasis.
• Taking T cells beyond the diffraction limit
  - Nature Immunology 11(1):51-52 (2010)
  Recent advances in microscopy have enabled imaging of cell surface receptors at ever higher resolutions. A report using the latest technology now provides evidence that the T cell antigen receptor and the adaptor Lat are confined to small islands, which cluster together after triggering of the T cell antigen receptor.
• Research Highlights
  - Nature Immunology 11(1):53 (2010)
  
• Eli Sercarz 1934–2009
  - Nature Immunology 11(1):54 (2010)
  Eli Sercarz died 3 November 2009 at the age of 75. His life was full.
• Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry
  Travassos LH Carneiro LA Ramjeet M Hussey S Kim YG Magalhães JG Yuan L Soares F Chea E Le Bourhis L Boneca IG Allaoui A Jones NL Nuñez G Girardin SE Philpott DJ - Nature Immunology 11(1):55-62 (2010)
  Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. By a mechanism independent of the adaptor RIP2 and transcription factor NF-κB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. In cells homozygous for the Crohn's disease–associated NOD2 frameshift mutation, mutant Nod2 failed to recruit ATG16L1 to the plasma membrane and wrapping of invading bacteria by autophagosomes was impaired. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.
• Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1β production
  Poeck H Bscheider M Gross O Finger K Roth S Rebsamen M Hannesschläger N Schlee M Rothenfusser S Barchet W Kato H Akira S Inoue S Endres S Peschel C Hartmann G Hornung V Ruland J - Nature Immunology 11(1):63-69 (2010)
  Interleukin 1β (IL-1β) is a potent proinflammatory factor during viral infection. Its production is tightly controlled by transcription of Il1b dependent on the transcription factor NF-κB and subsequent processing of pro-IL-1β by an inflammasome. However, the sensors and mechanisms that facilitate RNA virus–induced production of IL-1β are not well defined. Here we report a dual role for the RNA helicase RIG-I in RNA virus–induced proinflammatory responses. Whereas RIG-I-mediated activation of NF-κB required the signaling adaptor MAVS and a complex of the adaptors CARD9 and Bcl-10, RIG-I also bound to the adaptor ASC to trigger caspase-1-dependent inflammasome activation by a mechanism independent of MAVS, CARD9 and the Nod-like receptor protein NLRP3. Our results identify the CARD9–Bcl-10 module as an essential component of the RIG-I-dependent proinflammatory response and establish RIG-I as a sensor able to activate the inflammasome in response to certain R! NA viruses.
• Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines
  Tseng PH Matsuzawa A Zhang W Mino T Vignali DA Karin M - Nature Immunology 11(1):70-75 (2010)
  Balanced production of type I interferons and proinflammatory cytokines after engagement of Toll-like receptors (TLRs), which signal through adaptors containing a Toll–interleukin 1 receptor (TIR) domain, such as MyD88 and TRIF, has been proposed to control the pathogenesis of autoimmune disease and tumor responses to inflammation. Here we show that TRAF3, a ubiquitin ligase that interacts with both MyD88 and TRIF, regulated the production of interferon and proinflammatory cytokines in different ways. Degradative ubiquitination of TRAF3 during MyD88-dependent TLR signaling was essential for the activation of mitogen-activated protein kinases (MAPKs) and production of inflammatory cytokines. In contrast, TRIF-dependent signaling triggered noncanonical TRAF3 self-ubiquitination that activated the interferon response. Inhibition of degradative ubiquitination of TRAF3 prevented the expression of all proinflammatory cytokines without affecting the interferon response.
• Enteric defensins are essential regulators of intestinal microbial ecology
  Salzman NH Hung K Haribhai D Chu H Karlsson-Sjöberg J Amir E Teggatz P Barman M Hayward M Eastwood D Stoel M Zhou Y Sodergren E Weinstock GM Bevins CL Williams CB Bos NA - Nature Immunology 11(1):76-82 (2010)
  Antimicrobial peptides are important effectors of innate immunity throughout the plant and animal kingdoms. In the mammalian small intestine, Paneth cell α-defensins are antimicrobial peptides that contribute to host defense against enteric pathogens. To determine if α-defensins also govern intestinal microbial ecology, we analyzed the intestinal microbiota of mice expressing a human α-defensin gene (DEFA5) and in mice lacking an enzyme required for the processing of mouse α-defensins. In these complementary models, we detected significant α-defensin-dependent changes in microbiota composition, but not in total bacterial numbers. Furthermore, DEFA5-expressing mice had striking losses of segmented filamentous bacteria and fewer interleukin 17 (IL-17)-producing lamina propria T cells. Our data ascribe a new homeostatic role to α-defensins in regulating the makeup of the commensal microbiota.
• Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells
  Pepper M Linehan JL Pagán AJ Zell T Dileepan T Cleary PP Jenkins MK - Nature Immunology 11(1):83-89 (2010)
  We used a sensitive method based on tetramers of peptide and major histocompatibility complex II (pMHCII) to determine whether CD4+ memory T cells resemble the T helper type 1 (TH1) and interleukin 17 (IL-17)-producing T helper (TH17) subsets described in vitro. Intravenous or intranasal infection with Listeria monocytogenes induced pMHCII-specific CD4+ naive T cells to proliferate and produce effector cells, about 10% of which resembled TH1 or TH17 cells, respectively. TH1 cells were also present among the memory cells that survived 3 months after infection, whereas TH17 cells disappeared. The short lifespan of TH17 cells was associated with small amounts of the antiapoptotic protein Bcl-2, the IL-15 receptor and the receptor CD27, and little homeostatic proliferation. These results suggest that TH1 cells induced by intravenous infection are more efficient at entering the memory pool than are TH17 cells induced by intranasal infection.
• TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation
  - Nature Immunology 11(1):90-96 (2010)
  The organization and dynamics of receptors and other molecules in the plasma membrane are not well understood. Here we analyzed the spatio-temporal dynamics of T cell antigen receptor (TCR) complexes and linker for activation of T cells (Lat), a key adaptor molecule in the TCR signaling pathway, in T cell membranes using high-speed photoactivated localization microscopy, dual-color fluorescence cross-correlation spectroscopy and transmission electron microscopy. In quiescent T cells, both molecules existed in separate membrane domains (protein islands), and these domains concatenated after T cell activation. These concatemers were identical to signaling microclusters, a prominent hallmark of T cell activation. This separation versus physical juxtapositioning of receptor domains and domains containing downstream signaling molecules in quiescent versus activated T cells may be a general feature of plasma membrane–associated signal transduction.
• Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection
  - Nature Immunology 11(1):97 (2010)
  Introduction Nat. Immunol. 10, 831–839 (2009); published online 13 July 2009; corrected after print 19 August 2009 In the version of this article initially published, the top right graph in Figure 7b is incorrect. The error has been corrected in the HTML and PDF versions of the article.
• Thymic self-reactivity selects natural interleukin 17–producing T cells that can regulate peripheral inflammation
  - Nature Immunology 11(1):97 (2010)
  Introduction Nat. Immunol. 10, 1125–1132 (2009); published online 6 September 2009; corrected after print 5 October 2009 In the version of this article initially published, two relevant papers are not cited. The following brief description of the findings of these papers has been added to the end of the fourth full paragraph on page 1131, and the citations below are now included at the end of the reference list: "Our observations follow the identification in human thymi and umbilical cord blood of CD3+CD4+CD161+ cells that express RORγt, IL-23R and CCR6 and produce IL-17 after activation and stimulation with IL-1 and IL-23 (ref. 54). This work suggested that thymus-derived cells could be precursors of peripheral TH-17 cells in humans, an idea supported by the finding that CD161+IL-17+ cells can be isolated from the intestinal tissue of patients with Crohn's disease55." The error has been corrected in the HTML and PDF versions of the article.
• Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE
  - Nature Immunology 11(1):97 (2010)
  Introduction Nat. Immunol. 10, 958–964 (2009); published online 16 August 2009; corrected after print 18 September 2009 In the version of this article initially published, two citations were not included. These citations, together with text describing their content, have been added to page 958, column 2, as follows: "As neuronal loss is thought to contribute to the pathogenesis of progressive multiple sclerosis5, and as PARP-1 inhibitors suppress the incidence and severity of experimental autoimmune encephalomyelitis (EAE)36, 37, we investigated the function of 15-oxysterols in multiple sclerosis and EAE." The added references are as follows: The error has been corrected in the HTML and PDF versions of the article.
• Themis, a T cell–specific protein important for late thymocyte development
  - Nature Immunology 11(1):97 (2010)
  Introduction Nat. Immunol. 10, 840–847 (2009); published online 13 July 2009; corrected after print 19 August 2009 In the version of this article initially published, citation of the linked articles published in the same issue (ni.1769 and ni.1766) is missing. These should be cited on page 841 at the end of the first paragraph of the Results section. The error has been corrected in the HTML and PDF versions of the article.