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The Listeria internalin (Inl) A and B proteins are required for the bacteria to penetrate placental tissues, but only InlA is needed to breach the intestine. The enzyme PI3-K is also required for Listeria tissue invasion and is directly activated by InlB. Gessain et al. now show that PI3-K is constitutively active in intestinal tissue but not placental tissue, rendering InlB dispensable for intestinal invasion. The image illustrates Listeria (orange) invasion of human placental tissue, a process which involves Listeria InlA binding to its receptor E-cadherin (red). Artwork by Emilie Clark (Emilie@emilieclark.com).
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Brief Definitive Report
Flierl et al. show that phosphorothioate (PS) oligonucleotides activate platelets via interacting with the collagen receptor GPVI. As PS backbone modification is currently used for nucleotide-based drug candidates, the findings suggest that this widely used method may present a risk to patients in the form of arterial thrombosis.
VEGF-A production in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints involved with CD8+ T cell exhaustion, which can be reversed with anti-VEGF/VEGFR treatment.
Bee and wasp venom generate small neoantigens via phospholipase A2 that activate human T cells via CD1a presentation.
Gessain et al. explore how Listeria monocytogenes facilitates disseminated infection through host epithelial barriers using two of its surface proteins, InlA and InlB. By combining in vitro and in vivo approaches using intestinal and placental mouse and human tissues, they find a differential requirement for InlA and InlB in tissue invasiveness, with a critical role for PI3K activation.
Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IκBα
Mooster et al. created a knock-in mouse harboring a mutation (S32I) in IκBα that has been identified in a patient with ectodermal dysplasia with immunodeficiency. The mice are characterized by defective architectural cell function; they lack lymph nodes, Peyer’s patches, splenic marginal zones, and follicular DCs and fail to develop germinal centers. These features have not been previously recognized in patients.
Deficiency of the ubiquitin-editing enzyme A20 in the hematopoietic system causes anemia, lymphopenia, and postnatal lethality as the result of defective hematopoietic stem cell function.
ICOS signaling is required for inhibition of the transcription factor Klf2, which controls expression of genes expressed by follicular T helper (Tfh) cells. When ICOS signaling is blocked, Tfh cells lose expression of characteristic Tfh genes and revert to an effector phenotype, resulting in disruption of the germinal center response.
Follistatin-like 1 (Fstl1) is induced in response to lung injury and promotes the accumulation of myofibroblasts and subsequent fibrosis via regulation of TGF-β and BMP. Reducing Fstl1 in mice reduces bleomycin-induced fibrosis in vivo, offering a potential therapeutic target for progressive lung fibrosis.
PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness
Yang et al. provide new mechanistic insight into the role of kinase PDK1 in early NK cell development. Genetic deletion of PDK1 in mice led to a severe loss of NK cells and impaired antitumor activity in vivo. Their results indicate that PDK1 acts as a regulator of IL-15 signaling to induce expression of the circadian protein E4BP4, also modulating CD122 upregulation.
Jingsong Xu and colleagues investigate how neutrophils initiate polarized migration toward bacteria or chemoattractants. They find that attractant-induced activation of myosin phosphatase results in the deactivation of moesin at the prospective leading edge and its redistribution to the trailing edge, establishing polarity and directional pseudopod formation.
BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups