Hot off the presses! Dec 14 Immunity

The Dec 14 issue of the Immunity is now up on Pubget (About Immunity): 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:

• The Easy Virtue of CD1c
  - Immunity 33(6):831-833 (2010)
  CD1 molecules present lipid antigens to T cells. In this issue of Immunity, Scharf et al. (2010) solve the structure of CD1c, which has binding pockets suited for insertion of a variety of lipid antigens.
• CuRTAiling Interferon Regulatory Factor Signaling with the E3 Ligase RAUL
  - Immunity 33(6):833-835 (2010)
  Interferon regulatory factor 3 (IRF3) and IRF7 modulate the transcription of type I interferon. In this issue of Immunity, Yu and Hayward (2010) identify RAUL, the bona fide ubiquitin ligase that regulates turnover of IRF3 and IRF7.
• Foxo1 and Foxo3 help Foxp3
  - Immunity 33(6):835-837 (2010)
  In this issue of Immunity, Kerdiles et al. (2010) report that Foxo transcription factors are essential for the development and function of Foxp3-expressing regulatory T (Treg) cells via controlling the expression of genes associated with Treg cell function.
• Treg's Alter Ego: An Accessory in Tumor Killing
  - Immunity 33(6):838-840 (2010)
  Foxp3+ regulatory T cells can manifest functional "reprogramming" during inflammation. In this issue of Immunity, Sharma et al. (2010) show how reprogramming is beneficial to CD8+ T cell immunity and how the tumor microenvironment inhibits this process.
• Does Deleting Dendritic Cells Delete Autoimmunity?
  - Immunity 33(6):840-842 (2010)
  A role for dendritic cells (DCs) in autoimmunity remains to be fully delineated. In this issue of Immunity, Teichmann et al. (2010) reveal critical functions for DCs in augmenting, but surprisingly not in initiating, spontaneous autoimmune disease.
• Ubiquitin Makes Its Mark on Immune Regulation
  - Immunity 33(6):843-852 (2010)
  Ubiquitination, the covalent attachment of ubiquitin molecules to proteins, is emerging as a widely utilized mechanism for rapidly regulating cell signaling. Recent studies indicate that ubiquitination plays potent roles in regulating a variety of signals in both innate and adaptive immune cells. Here, we will review recent studies of ubiquitin ligases, ubiquitin chain linkages, and ubiquitin binding proteins that highlight the diversity and specificity of ubiquitin dependent functions in immune cells. We will also review studies that shed light on how ubiquitination signals are integrated in cell-type-specific fashion to regulate the immune system in vivo.
• The 2.5 Å Structure of CD1c in Complex with a Mycobacterial Lipid Reveals an Open Groove Ideally Suited for Diverse Antigen Presentation
  - Immunity 33(6):853-862 (2010)
  CD1 molecules function to present lipid-based antigens to T cells. Here we present the crystal structure of CD1c at 2.5 Å resolution, in complex with the pathogenic Mycobacterium tuberculosis antigen mannosyl-β1-phosphomycoketide (MPM). CD1c accommodated MPM's methylated alkyl chain exclusively in the A′ pocket, aided by a unique exit portal underneath the α1 helix. Most striking was an open F′ pocket architecture lacking the closed cavity structure of other CD1 molecules, reminiscent of peptide binding grooves of classical major histocompatibility complex molecules. This feature, combined with tryptophan-fluorescence quenching during loading of a dodecameric lipopeptide antigen, provides a compelling model by which both the lipid and peptide moieties of the lipopeptide are involved in CD1c presentation of lipopeptides.
• The Ubiquitin E3 Ligase RAUL Negatively Regulates Type I Interferon through Ubiquitination of the Transcription Factors IRF7 and IRF3
  - Immunity 33(6):863-877 (2010)
  In the course of combating infectious agents, type I interferon (IFN) needs a timely downregulation mechanism to avoid detrimental overreaction. Here we showed a mechanism for restraining type I IFN responses, which relied on a HECT domain ubiquitin (Ub) E3 ligase, RAUL. RAUL limited type I IFN production by directly catalyzing lysine 48-linked polyubiquitination of both interferon regulatory factor 7 (IRF7) and IRF3 followed by proteasome-dependent degradation. Suppression of RAUL by dominant-negative RAUL or siRNA augmented both basal and virus-induced production of type I IFN, which resulted in reduced viral replication. The Kaposi's sarcoma-associated herpes virus immediate-early lytic cycle trigger protein RTA recruited this mechanism to augment its countermeasures against the host antiviral response. These results unveil a previously unrecognized "brake mechanism" for type I IFN that maintains proper low amounts of type I IFN under physiological conditions an! d restrains its magnitude when the antiviral response intensifies.
• Glycogen Synthase Kinase 3β Regulates IRF3 Transcription Factor-Mediated Antiviral Response via Activation of the Kinase TBK1
  - Immunity 33(6):878-889 (2010)
  Viral infection activates transcription factors IRF3 and NF-κB, which collaborate to induce type I interferons (IFNs). Here, we identified glycogen synthase kinase 3β (GSK3β) as an important regulator for virus-triggered IRF3 and NF-κB activation, IFN-β induction, and cellular antiviral response. Overexpression of GSK3β potentiated virus-induced activation of IRF3 and transcription of the IFNB1 gene, whereas reduced expression or deletion of GSK3β impaired virus-induced IRF3 and NF-κB activation, transcription of the IFNB1 gene, as well as cellular antiviral response. GSK3β physically associated with the kinase TBK1 in a viral infection-dependent manner. GSK3β promoted TBK1 self-association and autophosphorylation at Ser172, which is critical for virus-induced IRF3 activation and IFN-β induction. The effect of GSK3β on virus-induced signaling is independent of its kinase activity. Our findings suggest that GSK3β plays important roles in virus-triggered IRF! 3 activation by promoting TBK1 activation and provide new insights to the molecular mechanisms of cellular antiviral response.
• Foxo Transcription Factors Control Regulatory T Cell Development and Function
  - Immunity 33(6):890-904 (2010)
  Foxo transcription factors integrate extrinsic signals to regulate cell division, differentiation and survival, and specific functions of lymphoid and myeloid cells. Here, we showed the absence of Foxo1 severely curtailed the development of Foxp3+ regulatory T (Treg) cells and those that developed were nonfunctional in vivo. The loss of function included diminished CTLA-4 receptor expression as the Ctla4 gene was a direct target of Foxo1. T cell-specific loss of Foxo1 resulted in exocrine pancreatitis, hind limb paralysis, multiorgan lymphocyte infiltration, anti-nuclear antibodies and expanded germinal centers. Foxo-mediated control over Treg cell specification was further revealed by the inability of TGF-β cytokine to suppress T-bet transcription factor in the absence of Foxo1, resulting in IFN-γ secretion. In addition, the absence of Foxo3 exacerbated the effects of the loss of Foxo1. Thus, Foxo transcription factors guide the contingencies of T cell differentiati! on and the specific functions of effector cell populations.
• Continuous Expression of the Transcription Factor E2-2 Maintains the Cell Fate of Mature Plasmacytoid Dendritic Cells
  - Immunity 33(6):905-916 (2010)
  The interferon-producing plasmacytoid dendritic cells (pDCs) share common progenitors with antigen-presenting classical dendritic cells (cDCs), yet they possess distinct morphology and molecular features resembling those of lymphocytes. It is unclear whether the unique cell fate of pDCs is actively maintained in the steady state. We report that the deletion of transcription factor E2-2 from mature peripheral pDCs caused their spontaneous differentiation into cells with cDC properties. This included the loss of pDC markers, increase in MHC class II expression and T cell priming capacity, acquisition of dendritic morphology, and induction of cDC signature genes. Genome-wide chromatin immunoprecipitation revealed direct binding of E2-2 to key pDC-specific and lymphoid genes, as well as to certain genes enriched in cDCs. Thus, E2-2 actively maintains the cell fate of mature pDCs and opposes the "default" cDC fate, in part through direct regulation of lineage-specific g! ene expression programs.
• Transcription Factor Miz-1 Is Required to Regulate Interleukin-7 Receptor Signaling at Early Commitment Stages of B Cell Differentiation
  - Immunity 33(6):917-928 (2010)
  B cell development requires the coordinated action of transcription factors and cytokines, in particular interleukin-7 (IL-7). We report that mice lacking the POZ (Poxvirus and zinc finger) domain of the transcription factor Miz-1 (Zbtb17ΔPOZ/ΔPOZ) almost entirely lacked follicular B cells, as shown by the fact that their progenitors failed to activate the Jak-Stat5 pathway and to upregulate the antiapoptotic gene Bcl2 upon IL-7 stimulation. We show that Miz-1 exerted a dual role in the interleukin-7 receptor (IL-7R) pathway by directly repressing the Janus kinase (Jak) inhibitor suppressor of cytokine signaling 1 (Socs1) and by activating Bcl2 expression. Zbtb17ΔPOZ/ΔPOZ (Miz-1-deficient) B cell progenitors had low expression of early B cell genes as transcription factor 3 (Tcf3) and early B cell factor 1 (Ebf1) and showed a propensity for apoptosis. Only the combined re-expression of Bcl2 and Ebf1 could reconstitute the ability of Miz-1-deficient precursors to de! velop into CD19+ B cells.
• An Oscillatory Switch in mTOR Kinase Activity Sets Regulatory T Cell Responsiveness
  - Immunity 33(6):929-941 (2010)
  There is a discrepancy between the in vitro anergic state of CD4+CD25hiFoxP3+ regulatory T (Treg) cells and their in vivo proliferative capability. The underlying mechanism of this paradox is unknown. Here we show that the anergic state of Treg cells depends on the elevated activity of the mammalian target of rapamycin (mTOR) pathway induced by leptin: a transient inhibition of mTOR with rapamycin, before T cell receptor (TCR) stimulation, made Treg cells highly proliferative in the absence of exogenous interleukin-2 (IL-2). This was a dynamic and oscillatory phenomenon characterized by an early downregulation of the leptin-mTOR pathway followed by an increase in mTOR activation necessary for Treg cell expansion to occur. These data suggest that energy metabolism, through the leptin-mTOR-axis, sets responsiveness of Treg cells that use this information to control immune tolerance and autoimmunity.
• Reprogrammed Foxp3+ Regulatory T Cells Provide Essential Help to Support Cross-presentation and CD8+ T Cell Priming in Naive Mice
  - Immunity 33(6):942-954 (2010)
  Foxp3+ regulatory T (Treg) cells can undergo reprogramming into a phenotype expressing proinflammatory cytokines. However, the biologic significance of this conversion remains unclear. We show that large numbers of Treg cells undergo rapid reprogramming into activated T helper cells after vaccination with antigen plus Toll-like receptor 9 (TLR-9) ligand. Helper activity from converted Treg cells proved essential during initial priming of CD8+ T cells to a new cross-presented antigen. Help from Treg cells was dependent on CD40L, and (unlike help from conventional non-Treg CD4+ cells) did not require preactivation or prior exposure to antigen. In hosts with established tumors, Treg cell reprogramming was suppressed by tumor-induced indoleamine 2,3-dioxygenase (IDO) and vaccination failed because of lack of help. Treg cell reprogramming, vaccine efficacy, and antitumor CD8+ T cell responses were restored by pharmacologic inhibition of IDO. Reprogrammed Treg cells can thus! participate as previously unrecognized drivers of certain early CD8+ T cell responses.
• Plasmacytoid Dendritic Cell Ablation Impacts Early Interferon Responses and Antiviral NK and CD8+ T Cell Accrual
  - Immunity 33(6):955-966 (2010)
  Plasmacytoid dendritic cells (pDCs) mediate type I interferon (IFN-I) responses to viruses that are recognized through the Toll-like receptor 7 (TLR7) or TLR9 signaling pathway. However, it is unclear how pDCs regulate the antiviral responses via innate and adaptive immune cells. We generated diphtheria toxin receptor transgenic mice to selectively deplete pDCs by administration of diphtheria toxin. pDC-depleted mice were challenged with viruses known to activate pDCs. In murine cytomegalovirus (MCMV) infection, pDC depletion reduced early IFN-I production and augmented viral burden facilitating the expansion of natural killer (NK) cells expressing the MCMV-specific receptor Ly49H. During vesicular stomatitis virus (VSV) infection, pDC depletion enhanced early viral replication and impaired the survival and accumulation of virus-specific cytotoxic T lymphocytes. We conclude that pDCs mediate early antiviral IFN-I responses and influence the accrual of virus-specific NK! or CD8+ T cells in a virus-dependent manner.
• Dendritic Cells in Lupus Are Not Required for Activation of T and B Cells but Promote Their Expansion, Resulting in Tissue Damage
  - Immunity 33(6):967-978 (2010)
  Dendritic cells (DCs) initiate and control the adaptive immune response against infections. However, their contributions to the anti-self adaptive immune response in autoimmune disorders like systemic lupus erythematosus are uncertain. By constitutively deleting DCs in MRL.Faslpr mice, we show that they have complex roles in murine lupus. The net effect of DC deletion was to ameliorate disease. DCs were crucial for the expansion and differentiation of T cells but, surprisingly, not required for their initial activation. Correspondingly, kidney interstitial infiltrates developed in the absence of DCs, but failed to progress. DC deletion concomitantly decreased inflammatory and regulatory T cell numbers. Unexpectedly, plasmablast numbers and autoantibody concentrations depended on DCs, in contrast to total serum immunoglobulin concentrations, suggesting an effect of DCs on extrafollicular humoral responses. These findings reveal that DCs operate in unanticipated ways in ! murine lupus and validate them as a potential therapeutic target in autoimmunity.