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Apoptosis by Incomplete Infection

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Apoptosis by Incomplete Infection rESEArcH HIGHLIGHtS Apoptosis by incomplete infection Constraining inflammation κ Infection with human immunodeficiency virus (HIV) is The transcription factor NF- B is a critical mediator of Toll-like recep- characterized by progressive apoptosis of CD4+ T cells, and tor (TLR) signaling in response to a range of activators. In Genes & although some of the molecular participants in this process are Development, Barish et al. provide genetic and genomic evidence that known, the precise details remain unclear. Greene and colleagues the transcription factor Bcl-6 broadly antagonizes the TLR–NF-κB in Cell report the unexpected finding that nonproductive infection network. Genome-wide expression analyses and chromatin-immuno- of CD4+ T cells can also result in apoptosis. The authors use a precipitation sequencing (ChIP-Seq) show that Bcl-6 is a basal- and human lymphoid aggregation culture system to recapitulate in lipopolysaccharide (LPS)-induced inhibitor of many inflammatory vitro the events of HIV infection in the lymph node. The addition modules in bone marrow–derived macrophages. Bcl-6 controls one of HIV to this culture system results in the apoptosis of not only third of the LPS-elicited transcriptome, and sites for Bcl-6 and the productively infected but also nonpermissive CD4+ cells. Apoptosis NF-κB subunit p65 are located together in a nucleosomal window of the latter requires fusion with HIV and the initiation but not (200 base pairs) in 25% of the gene network controlled by TLR–NF-κB. completion of viral reverse transcription. The accumulation Stimulation of TLR4 reciprocally diminishes or enhances the binding of of incomplete HIV reverse transcripts results in activation of Bcl-6 and p65 to enhancer regions at target genes encoding key inflam- caspase-1 and caspase-3 and release of the inflammatory cytokine matory molecules, such as IL-1 and various chemokines. Epigenetic IL-1β, which ultimately results in apoptosis. This may represent signatures suggest that Bcl-6 repressive modules restrict NF-κB activa- a defense pathway initiated after viral infection, but could also tion by limiting basal and TLR-induced histone acetylation. IV underlie the immune exhaustion seen during HIV infection. ZF Genes Dev. (24 November 2010) doi:10.1101/gad.1998010 Cell 143, 789–801 (2010) Tuning the inflammasome Early tolerance The NLRP3 inflammasome is an extensively studied molecular platform In humans, functional T cells begin to appear by week 10 of required for the maturation and release of the inflammatory cytokines gestation, but whether functionally distinct waves of T cells IL-1β and IL-18. Much is known about the activation of NLRP3, but are generated is uncertain. In Science, Mold et al. show that less is known about its regulation, which is what Sun and colleagues human fetal hematopoietic stem cell progenitors have a greater set out to address in the Journal of Immunology. The tripartite-motif propensity to become regulatory T cells (Treg cells) than do adult protein TRIM30 negatively regulates Toll-like receptor (TLR) sig- progenitors. In immunodeficient SCID mice transplanted with nals, and in the present study the authors observe that knockdown of organs of the human immune system, engraftment with fetal + TRIM30 boosts NLRP3 activation in response to many classic inflam- liver or bone marrow cells yields higher frequencies of Foxp3 + masome stimuli. Conversely, overexpression of TRIM30 attenuates CD25 Treg cells than does engraftment with adult bone marrow. inflammasome activation both in vitro and in vivo. Reactive oxygen In vitro suppression assays show that these fetal Treg cells are fully functional in blunting cytokine production and the proliferation of species (ROS) are important for full activation of the inflammasome, effector T cells. Gene profiling suggests that naive CD4+ T cells and TRIM30 seems to mediate its effects by modulating the generation Nature America, Inc. All rights reserved. All rights Inc. America, Nature that arise from human fetal cells are noticeably different from 1 of ROS. The molecular details of how TRIM30 modulates ROS remain 1 those that arise from adult bone marrow, with the former being unclear, but these findings reinforce the proposal that it acts as a potent more similar to adult T cells. Thus, a tolerogenic wave of T cells anti-inflammatory molecule. ZF reg © 20 appears early in the ontogeny of human T lineages and is probably J. Immunol. 185, 7699–7705 (2010) essential for tolerance to maternal antigens. LAD Science 330, 1695–1699 (2010) pDCs in wound healing Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferon in response to viral infection because of their ability to recognize single-stranded viral RNA and DNA via TLR7 Regulating NK activity and TLR9. In the Journal of Experimental Medicine, Gilliet Natural killer (NK) cells contribute to the elimination of transformed or and colleagues find that pDCs rapidly and transiently infiltrate infected cells through the targeted release of cytolytic granules contain- injured skin and contribute to wound healing. Infiltrating pDCs ing perforin and granzymes. In Blood, Caligiuri and colleagues show are activated by self nucleic acids from damaged cells acting that expression of these cytolytic proteins is governed by interaction of through TLR7 and TLR9. This break in self-tolerance is mediated the protein phosphatase PP2A with its negative regulator SET. PP2A by cathelicidin peptides, which are induced in injured skin and inhibits the expression of both granzyme B and perforin. Human CD56+ can convert inert nucleic acids into TLR triggers. The production NK cells activated with either interleukin 2 (IL-2) or IL-15 upregulate of type I interferon by activated pDCs is required for the induction SET protein and enhance cytolytic activity. Knockdown of endogenous of an early inflammatory response and wound re-epithelization. SET leads to more PP2A and less cytolytic function; conversely, SET Infiltration by pDCs is observed in both mechanical and chemical overexpression decreases PP2A expression, which in turn increases injury in mouse and human skin. Continuous production of granzyme expression and enhances the killing of tumor cell targets by cathelicidin and chronic pDC infiltration in psoriatic skin has been NK cells. Direct modulation of PP2A activity with agonists or inhibi- reported before. IV tors similarly affects granzyme expression and NK cell cytolytic activity. J. Exp. Med. (29 November 2010) doi:10.1084/jem.20101102 These results suggest that cytokine activation of NK cells enhances their cytolytic activity by relieving the PP2A block. LAD Written by Laurie A. Dempsey, Zoltan Fehervari & Ioana Visan Blood (14 December 2010) doi:10.1182/blood-2010-05-285130 NATURE IMMUNOLOGY VOLUME 12 NUMBER 2 FEBRUARY 2011 119.
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