Hot off the presses! Sep 01 Nat Immunol

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Latest Articles Include:

• Encouraging minority scientists
  - Nat Immunol 10(9):927 (2009)
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• From IL-10 to IL-12: how pathogens and their products stimulate APCs to induce TH1 development
  - Nat Immunol 10(9):929-932 (2009)
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• Intrusive HIV-1-infected cells
  - Nat Immunol 10(9):933-934 (2009)
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• The sickness unto Deaf
  - Nat Immunol 10(9):934-936 (2009)
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• Maintaining immune homeostasis in fly gut
  - Nat Immunol 10(9):936-938 (2009)
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• Regulatory T cells that become autoaggressive
  - Nat Immunol 10(9):938-939 (2009)
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• Research Highlights
  - Nat Immunol 10(9):941 (2009)
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• Foamy macrophages and the progression of the human tuberculosis granuloma
  - Nat Immunol 10(9):943-948 (2009)
  The progression of tuberculosis from a latent, subclinical infection to active disease that culminates in the transmission of infectious bacilli is determined locally at the level of the granuloma. This progression takes place even in the face of a robust immune response that, although it contains infection, is unable to eliminate the bacterium. The factors or environmental conditions that influence this progression remain to be determined. Recent advances have indicated that pathogen-induced dysregulation of host lipid synthesis and sequestration serves a critical role in this transition. The foamy macrophage seems to be a key participant in both sustaining persistent bacteria and contributing to the tissue pathology that leads to cavitation and the release of infectious bacilli.
• Coordination of multiple dual oxidase–regulatory pathways in responses to commensal and infectious microbes in drosophila gut
  - Nat Immunol 10(9):949-957 (2009)
  All metazoan guts are in permanent contact with the microbial realm. However, understanding of the exact mechanisms by which the strength of gut immune responses is regulated to achieve gut-microbe mutualism is far from complete. Here we identify a signaling network composed of complex positive and negative mechanisms that controlled the expression and activity of dual oxidase (DUOX), which 'fine tuned' the production of microbicidal reactive oxygen species depending on whether the gut encountered infectious or commensal microbes. Genetic analyses demonstrated that negative and positive regulation of DUOX was required for normal host survival in response to colonization with commensal and infectious microbes, respectively. Thus, the coordinated regulation of DUOX enables the host to achieve gut-microbe homeostasis by efficiently combating infection while tolerating commensal microbes.
• Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE
  - Nat Immunol 10(9):958-964 (2009)
  Multiple sclerosis is an inflammatory disease of the central nervous system that begins as a relapsing-remitting disease (RRMS) and is followed by a progressive phase (SPMS). The progressive phase causes the greatest disability and has no effective therapy, but the processes that drive SPMS are mostly unknown. Here we found higher serum concentrations of 15-hydroxicholestene (15-HC) in patients with SPMS and in mice with secondary progressive experimental autoimmune encephalomyelitis (EAE) but not in patients with RRMS. In mice, 15-HC activated microglia, macrophages and astrocytes through a pathway involving Toll-like receptor 2 (TLR2) and poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 activity was higher in monocytes of patients with SPMS, and PARP-1 inhibition suppressed the progression of EAE. Thus, the TLR2–PARP-1 pathway is a potential new therapeutic target in SPMS.
• TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis
  - Nat Immunol 10(9):965-972 (2009)
  The intensity and duration of immune responses are controlled by many proteins that modulate Toll-like receptor (TLR) signaling. TANK has been linked to positive regulation of the transcription factors IRF3 and NF-B. Here we demonstrate that TANK is not involved in interferon responses and is a negative regulator of proinflammatory cytokine production induced by TLR signaling. TLR-induced polyubiquitination of the ubiquitin ligase TRAF6 was upregulated in Tank-/- macrophages. Notably, Tank-/- mice spontaneously developed fatal glomerulonephritis owing to deposition of immune complexes. Autoantibody production in Tank-/- mice was abrogated by antibiotic treatment or the absence of interleukin 6 (IL-6) or the adaptor MyD88. Our results demonstrate that constitutive TLR signaling by intestinal commensal microflora is suppressed by TANK.
• Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells
  Dong Z Cruz-Munoz ME Zhong MC Chen R Latour S Veillette A - Nat Immunol 10(9):973-980 (2009)
  The adaptors SAP, EAT-2 and ERT are specific to cells of the immune system and belong to the SAP family. All three are expressed in natural killer (NK) cells. Here we examined the global function of the SAP family using mice lacking SAP, EAT-2 and ERT. These adaptors acted together in a mechanism that was essential for the elimination of hematopoietic but not nonhematopoietic cells by NK cells. This function was mediated by many receptors of the SLAM family on NK cells that were engaged by ligands found solely on hematopoietic cells. In the absence of SAP-related adaptors, SLAM receptors lost their activating function and became inhibitory receptors that repressed other activating receptors, such as NKG2D. Hence, the SAP family is essential for the elimination of unwanted hematopoietic cells by NK cells.
• Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10
  - Nat Immunol 10(9):981-991 (2009)
  Despite their central function in orchestrating immunity, dendritic cells (DCs) can respond to inhibitory signals by becoming tolerogenic. Here we show that galectin-1, an endogenous glycan-binding protein, can endow DCs with tolerogenic potential. After exposure to galectin-1, DCs acquired an interleukin 27 (IL-27)-dependent regulatory function, promoted IL-10-mediated T cell tolerance and suppressed autoimmune neuroinflammation. Consistent with its regulatory function, galectin-1 had its highest expression on DCs exposed to tolerogenic stimuli and was most abundant from the peak through the resolution of autoimmune pathology. DCs lacking galectin-1 had greater immunogenic potential and an impaired ability to halt inflammatory disease. Our findings identify a tolerogenic circuit linking galectin-1 signaling, IL-27-producing DCs and IL-10-secreting T cells, which has broad therapeutic implications in immunopathology.
• T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-
  Yu Q Sharma A Oh SY Moon HG Hossain MZ Salay TM Leeds KE Du H Wu B Waterman ML Zhu Z Sen JM - Nat Immunol 10(9):992-999 (2009)
  The differentiation of activated CD4+ T cells into the T helper type 1 (TH1) or TH2 fate is regulated by cytokines and the transcription factors T-bet and GATA-3. Whereas interleukin 12 (IL-12) produced by antigen-presenting cells initiates the TH1 fate, signals that initiate the TH2 fate are not completely characterized. Here we show that early GATA-3 expression, required for TH2 differentiation, was induced by T cell factor 1 (TCF-1) and its cofactor -catenin, mainly from the proximal Gata3 promoter upstream of exon 1b. This activity was induced after T cell antigen receptor (TCR) stimulation and was independent of IL-4 receptor signaling through the transcription factor STAT6. Furthermore, TCF-1 blocked TH1 fate by negatively regulating interferon- (IFN-) expression independently of -catenin. Thus, TCF-1 initiates TH2 differentiation of activated CD4+ T cells by promoting GATA-3 expression and suppressing IFN- expression.
• Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo
  Zhou X Bailey-Bucktrout SL Jeker LT Penaranda C Martínez-Llordella M Ashby M Nakayama M Rosenthal W Bluestone JA - Nat Immunol 10(9):1000-1007 (2009)
  Regulatory T cells (Treg cells) are central to the maintenance of immune homeostasis. However, little is known about the stability of Treg cells in vivo. In this study, we demonstrate that a substantial percentage of cells had transient or unstable expression of the transcription factor Foxp3. These 'exFoxp3' T cells had an activated-memory T cell phenotype and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers were higher in inflamed tissues in autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid onset of diabetes. Finally, analysis of the T cell receptor repertoire suggested that exFoxp3 cells developed from both natural and adaptive Treg cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.
• HIV-1 evades virus-specific IgG2 and IgA responses by targeting systemic and intestinal B cells via long-range intercellular conduits
  Xu W Santini PA Sullivan JS He B Shan M Ball SC Dyer WB Ketas TJ Chadburn A Cohen-Gould L Knowles DM Chiu A Sanders RW Chen K Cerutti A - Nat Immunol 10(9):1008-1017 (2009)
  Contact-dependent communication between immune cells generates protection but also facilitates viral spread. Here we found that macrophages formed long-range actin-propelled conduits in response to negative factor (Nef), a human immunodeficiency virus type 1 (HIV-1) protein with immunosuppressive functions. Conduits attenuated immunoglobulin G2 (IgG2) and IgA class switching in systemic and intestinal lymphoid follicles by shuttling Nef from infected macrophages to B cells through a guanine-exchange factor–dependent pathway involving the amino-terminal anchor, central core and carboxy-terminal flexible loop of Nef. By showing stronger virus-specific IgG2 and IgA responses in patients with Nef-deficient virions, our data suggest that HIV-1 exploits intercellular 'highways' as a 'Trojan horse' to deliver Nef to B cells and evade humoral immunity systemically and at mucosal sites of entry.
• Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor–intrinsic costimulation to class-switched B cells
  - Nat Immunol 10(9):1018-1025 (2009)
  The improved antibody responses of class-switched memory B cells depend on enhanced signaling from their B cell antigen receptors (BCRs). However, BCRs on both naive and antigen-experienced B cells use the canonical immunoglobulin-associated and -protein signaling subunits. Here we identified a BCR isotype–specific signal-amplification mechanism. Whereas immunoglobulin M (IgM)-containing BCRs initiated intracellular signals exclusively through immunoglobulin-associated - and -proteins, IgG- and IgE-containing BCRs also used a conserved tyrosine residue in the cytoplasmic segments of immunoglobulin heavy chains. When phosphorylated, this tyrosine recruited the adaptor Grb2, resulting in sustained protein kinase activation and prolonged generation of second messengers, which together culminated in enhanced B cell proliferation. Hence, membrane-bound IgG and IgE exert antigen recognition as well as costimulatory functions, thereby rendering memory B cells less dependen! t on T cell help.
• Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes
  - Nat Immunol 10(9):1026-1033 (2009)
  Type 1 diabetes may result from a breakdown in peripheral tolerance that is partially controlled by the expression of peripheral tissue antigens (PTAs) in lymph nodes. Here we show that the transcriptional regulator Deaf1 controls the expression of genes encoding PTAs in the pancreatic lymph nodes (PLNs). The expression of canonical Deaf1 was lower, whereas that of an alternatively spliced variant was higher, during the onset of destructive insulitis in the PLNs of nonobese diabetic (NOD) mice. We identified an equivalent variant Deaf1 isoform in the PLNs of patients with type 1 diabetes. Both the NOD mouse and human Deaf1 variant isoforms suppressed PTA expression by inhibiting the transcriptional activity of canonical Deaf1. Lower PTA expression resulting from the alternative splicing of DEAF1 may contribute to the pathogenesis of type 1 diabetes.
• Corrigendum: RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci
  - Nat Immunol 10(9):1034 (2009)
  Introduction Nature Immunology; 10, 655–664 (2009); published online 17 May 2009; corrected after print 18 May 2009 In the version of this article initially published, some of the funding was stated incorrectly or missing; the Competing Financial Interests section was missing; and the citation to reference 15 was missing. The correct funding statement should be as follows: Supported by the Wellcome Trust (085096 to J.A.S.), the New York University School of Medicine (J.A.S.), the US National Institutes of Health (R37 AI32524 to D.G.S.; R01 GM086852A to J.A.S.; R01 CA125195 to C.H.B.; and RO1 AI050737 to M.A.F.), the Pew Scholars Program (C.H.B. and M.A.F.), the Cancer Research Institute (M.A.F.), the Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology (B.Y.), Boehringer Ingelheim (M.B.), Genome Research in Austria (M.B.) and the Howard Hughes Medical Institute (D.G.S.). The correct Competing Financial Interests statement should be "The authors declare competing financial interests"; in the PDF, the statement also includes "details accompany the full-text HTML versio! n of the paper at http://www.nature.com/natureimmunology/." The citation for reference 15 should be on the first page as follows: "Studies of the rearrangement status of Igh alleles in mature B cell hybridomas and in developing B cells that have been transformed by Abelson murine leukemia virus15 have suggested...." The errors have been corrected in the HTML and PDF versions of the article.