Thursday, September 22, 2011

Hot off the presses! Sep 23 Immunity

The Sep 23 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:

  • Regulatory T Cells GATA Have It
    - Immunity 35(3):313-315 (2011)
    The factors that control regulatory T (Treg) cell homeostasis and function are still being defined. In this issue of Immunity, demonstrate that the Th2 cell-associated transcription factor GATA-3 helps control Foxp3 expression in Treg cells and is required for their proper functional activity in vivo.
  • Excitable T Cells: CaV1.4 Channel Contributions and Controversies
    - Immunity 35(3):315-317 (2011)
    Store-operated CRAC channels encoded by the Orai genes mediate calcium entry in T cells. In this issue of Immunity, record CaV1.4-mediated voltage-gated calcium currents in T cells and address their role for T cell development and function.
  • Nanocluster Formation: More with Memory
    - Immunity 35(3):318-320 (2011)
    The molecular basis of quicker and stronger responses by memory T cells is elusive. In this issue of Immunity, demonstrate that more T cell receptor nanoclusters are present on memory cells than naive T cells before antigen stimulation, suggesting a basis for quick memory response.
  • Mind Bomb Proteins in the Antiviral Arsenal
    - Immunity 35(3):320-322 (2011)
    In this issue of Immunity, reported a dynamic protein interactome network underlying antiviral innate immune response and established the role of Mind Bomb proteins in the anti-RNA viral innate immune response.
  • Dendritic Cell and Macrophage Heterogeneity In Vivo
    - Immunity 35(3):323-335 (2011)
    Macrophage and dendritic cell (DC) are hematopoietic cells found in all tissues in the steady state that share the ability to sample the environment but have distinct function in tissue immunity. Controversies remain on the best way to distinguish macrophages from DCs in vivo. In this Perspective, we discuss how recent discoveries in the origin of the DC and macrophage lineage help establish key functional differences between tissue DC and macrophage subsets. We also emphasize the need to further understand the functional heterogeneity of the tissue DC and macrophage lineages to better comprehend the complex role of these cells in tissue homeostasis and immunity.
  • An Essential Role of the Transcription Factor GATA-3 for the Function of Regulatory T Cells
    - Immunity 35(3):337-348 (2011)
    Forkhead Box P3 (Foxp3)-expressing regulatory T (Treg) cells are central to maintaining self-tolerance and immune homeostasis. How Treg cell function and Foxp3 expression are regulated is an important question under intensive investigation. Here, we have demonstrated an essential role for the transcription factor GATA-3, a previously recognized Th2 cell master regulator, in controlling Treg cell function. Treg cell-specific GATA-3 deletion led to a spontaneous inflammatory disorder in mice. GATA-3-null Treg cells were defective in peripheral homeostasis and suppressive function, gained Th17 cell phenotypes, and expressed reduced amounts of Foxp3. In addition, GATA-3 controlled Foxp3 expression by binding to and promoting the activity of cis-acting elements of Foxp3. Furthermore, the combined function of GATA-3 and Foxp3 was essential for Foxp3 expression. These findings provide insights into immune regulatory mechanisms and uncover a critical function of GATA-3 in Treg! cells and immune tolerance.
  • The CaV1.4 Calcium Channel Is a Critical Regulator of T Cell Receptor Signaling and Naive T Cell Homeostasis
    - Immunity 35(3):349-360 (2011)
    The transport of calcium ions (Ca2+) to the cytosol is essential for immunoreceptor signaling, regulating lymphocyte differentiation, activation, and effector function. Increases in cytosolic-free Ca2+ concentrations are thought to be mediated through two interconnected and complementary mechanisms: the release of endoplasmic reticulum Ca2+ "stores" and "store-operated" Ca2+ entry via plasma membrane channels. However, the identity of molecular components conducting Ca2+ currents within developing and mature T cells is unclear. Here, we have demonstrated that the L-type "voltage-dependent" Ca2+ channel CaV1.4 plays a cell-intrinsic role in the function, development, and survival of naive T cells. Plasma membrane CaV1.4 was found to be essential for modulation of intracellular Ca2+ stores and T cell receptor (TCR)-induced rises in cytosolic-free Ca2+, impacting activation of Ras-extracellular signal-regulated kinase (ERK) and nuclear factor of activated T ce! lls (NFAT) pathways. Collectively, these studies revealed that CaV1.4 functions in controlling naive T cell homeostasis and antigen-driven T cell immune responses.
  • Polarized Secretion of Lysosomes at the B Cell Synapse Couples Antigen Extraction to Processing and Presentation
    - Immunity 35(3):361-374 (2011)
    Engagement of the B cell receptor (BCR) by surface-tethered antigens (Ag) leads to formation of a synapse that promotes Ag uptake for presentation onto major histocompatibility complex class II (MHCII) molecules. We have highlighted the membrane trafficking events and associated molecular mechanisms involved in Ag extraction and processing at the B cell synapse. MHCII-containing lysosomes are recruited to the synapse where they locally undergo exocytosis, allowing synapse acidification and the extracellular release of hydrolases that promote the extraction of the immobilized Ag. Lysosome recruitment and secretion results from the polarization of the microtubule-organizing center (MTOC), which relies on the cell division cycle (Cdc42)-downstream effector, atypical protein kinase C (aPKCζ). aPKCζ is phosphorylated upon BCR engagement, associates to lysosomal vesicles, and is required for their polarized secretion at the B cell synapse. Regulation of B lymphocyte po! larity therefore emerges as a central mechanism that couples Ag extraction to Ag processing and presentation.
  • Increased Sensitivity of Antigen-Experienced T Cells through the Enrichment of Oligomeric T Cell Receptor Complexes
    - Immunity 35(3):375-387 (2011)
    Although memory T cells respond more vigorously to stimulation and they are more sensitive to low doses of antigen than naive T cells, the molecular basis of this increased sensitivity remains unclear. We have previously shown that the T cell receptor (TCR) exists as different-sized oligomers on the surface of resting T cells and that large oligomers are preferentially activated in response to low antigen doses. Through biochemistry and electron microscopy, we now showed that previously stimulated and memory T cells have more and larger TCR oligomers at the cell surface than their naive counterparts. Reconstitution of cells and mice with a point mutant of the CD3ζ subunit, which impairs TCR oligomer formation, demonstrated that the increased size of TCR oligomers was directly responsible for the increased sensitivity of antigen-experienced T cells. Thus, we propose that an "avidity maturation" mechanism underlies T cell antigenic memory.
  • The Signaling Adaptor Eps8 Is an Essential Actin Capping Protein for Dendritic Cell Migration
    - Immunity 35(3):388-399 (2011)
    Dendritic cells (DCs) flexibly adapt to different microenvironments by using diverse migration strategies that are ultimately dependent on the dynamics and structural organization of the actin cytoskeleton. Here, we have shown that DCs require the actin capping activity of the signaling adaptor Eps8 to polarize and to form elongated migratory protrusions. DCs from Eps8-deficient mice are impaired in directional and chemotactic migration in 3D in vitro and are delayed in reaching the draining lymph node (DLN) in vivo after inflammatory challenge. Hence, Eps8-deficient mice are unable to mount a contact hypersensitivity response. We have also shown that the DC migratory defect is cell autonomous and that Eps8 is required for the proper architectural organization of the actin meshwork and dynamics of cell protrusions. Yet, Eps8 is not necessary for antigen uptake, processing, and presentation. Thus, we have identified Eps8 as a unique actin capping protein specifically re! quired for DC migration.
  • Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T Cells
    - Immunity 35(3):400-412 (2011)
    Functionally exhausted T cells have high expression of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. By using human and murine systems of acute and chronic viral infections, we analyzed epigenetic regulation of PD-1 expression during CD8+ T cell differentiation. During acute infection, naive to effector CD8+ T cell differentiation was accompanied by a transient loss of DNA methylation of the Pdcd1 locus that was directly coupled to the duration and strength of T cell receptor signaling. Further differentiation into functional memory cells coincided with Pdcd1 remethylation, providing an adapted program for regulation of PD-1 expression. In contrast, the Pdcd1 regulatory region was completely demethylated in exhausted CD8+ T cells and remained unmethylated even when virus titers decreased. This lack of DNA remethylation leaves the Pdcd1 locus poised for rapid expression, potentially ! providing a signal for premature termination of antiviral functions.
  • Multilineage Priming of Enhancer Repertoires Precedes Commitment to the B and Myeloid Cell Lineages in Hematopoietic Progenitors
    - Immunity 35(3):413-425 (2011)
    Recent studies have documented genome-wide binding patterns of transcriptional regulators and their associated epigenetic marks in hematopoietic cell lineages. In order to determine how epigenetic marks are established and maintained during developmental progression, we have generated long-term cultures of hematopoietic progenitors by enforcing the expression of the E-protein antagonist Id2. Hematopoietic progenitors that express Id2 are multipotent and readily differentiate upon withdrawal of Id2 expression into committed B lineage cells, thus indicating a causative role for E2A (Tcf3) in promoting the B cell fate. Genome-wide analyses revealed that a substantial fraction of lymphoid and myeloid enhancers are premarked by the poised or active enhancer mark H3K4me1 in multipotent progenitors. Thus, in hematopoietic progenitors, multilineage priming of enhancer elements precedes commitment to the lymphoid or myeloid cell lineages.
  • Mapping a Dynamic Innate Immunity Protein Interaction Network Regulating Type I Interferon Production
    - Immunity 35(3):426-440 (2011)
    To systematically investigate innate immune signaling networks regulating production of type I interferon, we analyzed protein complexes formed after microbial recognition. Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions; 21% of interactions were modulated by RNA, DNA, or LPS. Overexpression and depletion analyses identified 22 unique genes that regulated NF-κB and ISRE reporter activity, viral replication, or virus-induced interferon production. Detailed mechanistic analysis defined a role for mind bomb (MIB) E3 ligases in K63-linked ubiquitination of TBK1, a kinase that phosphorylates IRF transcription factors controlling interferon production. Mib genes selectively controlled responses to cytosolic RNA. MIB deficiency reduced antiviral activity, establishing the role of MIB proteins as positive regulators of antiviral responses. The HI5 provides a dyna! mic physical and regulatory network that serves as a resource for mechanistic analysis of innate immune signaling.

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