ON THE COVER
Casanova-Acebes et al. show the role of neutrophils in homeostasis and pathological states. The image depicts an isolated lymphoid follicle of the intestinal mucosa in which neutrophils (green) accumulate and are surrounded by intestinal macrophages (red), with the follicle’s vasculature shown in the background. The image was provided by the authors. See page 2778.
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Deczkowska and Schwartz describe how harnessing the immune system in a well-controlled manner can be used as a universal therapeutic approach to neurodegeneration.
Brief Definitive Report
The mechanisms underlying the differentiation of T follicular helper (Tfh) cell subsets are poorly understood. Here, Fang et al. show that the NKG2Dhigh Tfh cells in germinal centers with a history of T-bet expression represent the IFN-γ–producing Tfh subset.
A novel germline missense mutation in human IKBKB (encoding IKK2) confers gain of function and results in a combined immune deficiency syndrome. A mouse model engineered by CRISPR/Cas9 to carry the orthologous mutation exhibits a similar cellular phenotype.
Human monocytes and macrophages regulate immune tolerance via integrin αvβ8–mediated TGFβ activation
TGFβ is a crucial immune regulator and attractive therapeutic target but needs to be activated to function. Kelly et al. show that human monocytes and macrophages activate TGFβ via expression of an integrin, αvβ8, which dampens pro-inflammatory cytokine production and is disrupted in inflammatory bowel disease.
Airway allergic responses are shown to be inhibited by binding of ABIN-2 to A20, a key negative regulator of inflammation. In contrast, the catalytic activity of the ABIN-2–associated kinase TPL-2 does not regulate airway allergic responses, an important consideration for the development of TPL-2 inhibitors to treat inflammatory diseases.
Technical Advances and Resources
Urine-derived lymphocytes (UDLs) may serve as a non-invasive dynamic biomarker, reflective of the immune checkpoint phenotype and T-cell receptor repertoire of tumor-infiltrating lymphocytes. Patients with UDLs expressing high levels of PD-1 had worse clinical outcomes in muscle invasive bladder cancer.
This work shows how blood and lymphatic vessels contribute to lymph node organogenesis. Both vessel types transport lymphoid tissue inducer cells, while lymphatics also generate interstitial flow, important for mechanical stromal activation and further lymph node expansion.
Neutrophils enter tissues to mediate immunity and inflammation. Casanova-Acebes et al. show that migration into naive tissues is equally important. In the intestine, they provide remote support to hematopoietic niches, whereas in the lungs they regulate circadian transcription and metastasis.
Fan et al. have identified a population of recirculating Treg cells with greater suppressive ability and a unique tissue distribution. Using single-cell RNA-seq, they place these Treg cells at the apex of the Treg developmental trajectory and show that similar cells may exist in humans.
The process whereby hematopoietic stem cells (HSCs) generate different blood cell types in the steady-state is poorly understood. Upadhaya et al. used inducible lineage tracing to characterize the earliest steps of adult HSC differentiation in vivo.
KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer
Wang et al. report an unexpected role of demethylase KDM4B in regulating unfolded protein response (UPR). A stepwise hyperactivation of UPR by co-targeting the KDM4B and PI3K pathway uncovers a therapeutic vulnerability of PTEN-deficient TNBC that otherwise would be resistant to PI3K inhibition.
Although usp38 has recently been reported to be in a chromosome locus associated with human asthma in a GWAS study, its potential pathological role remains unknown. Chen et al. now demonstrate that usp38 is essential for asthmatic pathogenesis. USP38 is induced by TCR signaling and in turn promotes JunB stabilization to specifically regulate Th2 cell differentiation.
Dysregulated autophagy and ER stress are involved in the etiology of human IBD. Aden et al. show that loss of ATG16L1 function renders intestinal epithelial cells vulnerable to IL-22–induced ER stress and necroptosis via STING signaling, which induces ileal inflammation in vivo.
Sox4 is shown to be essential for the development of natural killer T cells that function as innate-like first responders. Existence of specific gene circuits to tailor TCR signal-dependent thymic selection into the innate-like αβ T cell lineage is revealed.
NFAT5 regulates macrophage MHCII expression by controlling the transcription of its coactivator Ciita through a remote enhancer. This mechanism differs from those previously found in DCs and B lymphocytes and distinguishes macrophages from these APC lineages.
Cheng and Schorey identified a regulatory mechanism where cytosolic DNA and RNA sensing pathways synergistically regulate type I IFN production in macrophages and mice during a Mycobacterium tuberculosis infection and show that activation of mitochondrial antiviral signaling protein (MAVS) promotes M.tb survival in mice.
Peyer’s patch myeloid cells infection by Listeria signals through gp38+ stromal cells and locks intestinal villus invasion
Listeria monocytogenes (Lm) crosses the intestinal villus barrier via goblet cells (GCs). Disson et al. show that Lm infection of Peyer’s patch myeloid cells signals to villus stromal cells, leading to a decrease of GCs expressing luminally accessible E-cadherin, thereby blocking villus infection while favoring colitis.