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)
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• NKT cells turn ten
  - Nat Immunol 10(7):669-671 (2009)
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• NIAID workshop on immunity to malaria: addressing immunological challenges
  - Nat Immunol 10(7):673-678 (2009)
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• Basophils trump dendritic cells as APCs for TH2 responses
  - Nat Immunol 10(7):679-681 (2009)
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• CSF-1R, DAP12 and beta-catenin: a ménage à trois
  - Nat Immunol 10(7):681-683 (2009)
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• ASMase: the tailor of cytotoxic T cell granule exocytosis
  - Nat Immunol 10(7):683-685 (2009)
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• A novel modifier of regulatory T cells
  - Nat Immunol 10(7):685-686 (2009)
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• Research Highlights
  - Nat Immunol 10(7):687 (2009)
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• 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.