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.