Intracellular Toll-like Receptors

Foreign nucleic acids, the signature of invading viruses and certain bacteria, are sensed intracellularly. The nucleic acid-specific Toll-like receptors (TLRs) detect and signal within endolysosomal compartments, triggering the induction of cytokines essential for the innate immune response. These cytokines include proinflammatory molecules produced mainly by macrophages and conventional dendritic cells, as well as type I interferons, which are produced in great quantities by plasmacytoid dendritic cells. The cellular and molecular pathways by which nucleic acids and TLRs meet within the endosome assure host protection yet also place the host at risk for the development of autoimmunity. Here, we review the latest findings on the intracellular TLRs, with special emphasis on ligand uptake, receptor trafficking, signaling, and regulation

Development and function of murine B220+CD11c+NK1.1+ cells identify them as a subset of NK cells

Lymphoid organs contain a B220+CD11c+NK1.1+ cell population that was recently characterized as a novel dendritic cell (DC) subset that functionally overlaps with natural killer (NK) cells and plasmacytoid DCs (PDCs). Using Siglec-H and NK1.1 markers, we unambiguously dissected B220+CD11c+ cells and found that PDCs are the only professional interferon (IFN)-α–producing cells within this heterogeneous population. In contrast, B220+CD11c+NK1.1+ cells are a discrete NK cell subset capable of producing higher levels of IFN-γ than conventional NK cells. Unlike DCs, only a minute fraction of B220+CD11c+NK1.1+ cells in the spleen expressed major histocompatibility complex class II ex vivo or after stimulation with CpG. Consistent with being a NK cell subset, B220+CD11c+NK1.1+ cells depended primarily on interleukin 15 and common cytokine receptor γ chain signaling for their development. In terms of function, expression of distinctive cell surface receptors, and location in lymphoid organs, NK1.1+B220+CD11c+ appear to be the murine equivalent of human CD56bright NK cells

Slc15a4, a gene required for pDC sensing of TLR ligands, is required to control persistent viral infection

Plasmacytoid dendritic cells (pDCs) are the major producers of type I IFN in response to viral infection and have been shown to direct both innate and adaptive immune responses in vitro. However, in vivo evidence for their role in viral infection is lacking. We evaluated the contribution of pDCs to acute and chronic virus infection using the feeble mouse model of pDC functional deficiency. We have previously demonstrated that feeble mice have a defect in TLR ligand sensing. Although pDCs were found to influence early cytokine secretion, they were not required for control of viremia in the acute phase of the infection. However, T cell priming was deficient in the absence of functional pDCs and the virus-specific immune response was hampered. Ultimately, infection persisted in feeble mice. We conclude that pDCs are likely required for efficient T cell priming and subsequent viral clearance. Our data suggest that reduced pDC functionality may lead to chronic infection

Adhesive mechanisms governing interferon-producing cell recruitment into lymph nodes

Natural interferon-producing cells (IPCs) are found in peripheral lymph nodes (PLNs), where they support NK cell, T cell, and B cell responses to pathogens. However, their route of entry and the adhesive mechanisms used to gain access to PLNs remain poorly defined. We report that IPCs can enter PLNs via a hematogenous route, which involves a multistep adhesive process, and that transmigration is enhanced by inflammation. Results indicate that L-selectin on IPCs is required for efficient attachment and rolling on high endothelial venules in vivo in both nonstimulated and inflamed PLNs. IPCs, however, also possess functional ligands for E-selectin that contribute to this process only in the latter case. In conjunction with selectin-mediated adhesion, both β1- and β2-integrins participate in IPC attachment to the inflamed vessel wall, whereas chemotaxis relies in part on the chemokine receptor CCR5. Identification of the adhesive machinery required for IPC trafficking into PLNs may provide opportunities to regulate immune responses reliant on the activity of these cells

Inflammatory arthritis can be reined in by CpG-induced DC–NK cell cross talk

Unmethylated CpG-oligodeoxynucleotides (ODNs) are generally thought of as potent adjuvants with considerable therapeutic potential to enhance immune responses against microbes and tumors. Surprisingly, certain so-called stimulatory CpG-ODNs strongly inhibited the effector phase of inflammatory arthritis in the K/BxN serum transfer system, either preventively or therapeutically. Also unexpected was that the inhibitory influence did not depend on the adaptive immune system cells mobilized in an immunostimulatory context. Instead, they relied on cells of the innate immune system, specifically on cross talk between CD8α+ dendritic cells and natural killer cells, resulting in suppression of neutrophil recruitment to the joint, orchestrated through interleukin-12 and interferon-γ. These findings highlight potential applications of CpG-ODNs and downstream molecules as antiinflammatory agents

Crime de Realengo: o sutiã lilás na tromba do elefante verde e amarelo

Este    artigo,    escrito    a    seis    mãos    plugadas    à    rede,   examina, do    ponto    de    vista    dos    estudos    culturais:   linguagem    e    gênero,    o assassinato    de    12    adolescentes   brasileiros.    Esse    crime    ocorreu numa    única    ação,    dentro   de   uma    escola,    na    periferia    do    Rio    de Janeiro,    Cidade   Maravilhosa,    praticado    por    um    ex-aluno,    evento    que inaugurou    a    presença    do    Brasil    no    cenário    global    das   brutalidades gigantescas,     aquelas     fadadas     à     não-conclusão.     Isso,     dado     as inúmeras    variáveis    que    atravessam    as   tentativas    de    se    desenhar um    “elefante”,    sem    nunca    ter   visto    ou    sequer    tateado    o    animal.O     recorte     aqui     demarcado     e     o     problema     da     imprecisão     serão delineados    na    ciência    técnica    da   dificuldade    de    se    enxergar    para além    do    aparente,    bem   como    na    verificação    dos    perigos    inerentes    à banalização   de    um    crime    mediante    a    disputa    pela    informação    entre a    mídia    e    os    órgãos    investigativos    oficiais.    Quando,   ambos,    passam a    supor    ou    nomear    fatos    (terrorismo,   esquizofrenismo)    e    “coisas” (crianças-terroristas),    no    calor    da   emoção,    sem    distanciamento    e rigor,    ignoram,   respectivamente,    outras    possibilidades    (crime    de gênero-exclusão)    (jovens-mulheres)    e    legitimam    aquilo    que    o   senso comum    e    o    Ibope    alimentam.    Recorre-se,    como   tentativa    de    dirigir um    olhar    ampliado,    principalmente,    à   arte    cinematográfica    e    às lentes    de    aumento    de    Gus   Van    Sant4  (2003),    em    seu    documentário crítico    sobre    o   “similar    caso”    de    Columbine    (EUA)