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Starczynowski and colleagues show that myelodysplastic syndrome HSPCs have a competitive advantage as compared to normal HSPCs during chronic inflammation due to a switch from canonical to noncanonical signaling for the activation of NF-κB.
Oxidative stress can promote neurodegeneration. Akassoglou and colleagues describe Tox-seq, a functional single-cell RNA sequencing method to identify oxidative stress transcriptional signatures in CNS-resident cells. Tox-seq identified coagulation and glutathione-redox pathway genes that are coupled to oxidative stress and that could be targeted by the glutathione-regulating small molecule acivicin.
Savage and colleagues show virtual memory CD8 T cells arise in the thymus of replete mice, where their differentiation is a robust TCR-directed process. Clonal analyses show their TCR repertoire is reproducible and distinct from conventional cells and that progeny cells harboring such TCRs infiltrate tumors and express PD-1.
Human aging is characterized by an elevated basal inflammatory state.
Gilroy and colleagues use a tractable in vivo human inflammation model to
demonstrate a mechanism whereby efferocytosis is impaired in the elderly but is
reversible by p38 inhibition.
Therapeutic irradiation can trigger DNA-sensing pathways and trigger antitumor immunity. Fu and colleagues demonstrate that tumors can co-opt intrinsic apoptotic pathways to avoid immunogenic cell death following irradiation.
Autoreactive T cells are subject to continuous antigenic stimulation yet sustain their autoreactive functionality. Youngblood and colleagues examine type 1 diabetes systems to show that a pool of autoreactive CD8+ T cells exhibits a stem cell–like signature that facilitates their durable activity.
Akbar and colleagues show that sestrins induce the reprogramming of non-proliferative, senescent-like CD27–CD28–CD8+ T cells to acquire an innate-like killing activity modulated by the NK receptor NKG2D and the adaptor molecule DAP12.
The deubiquitinase A20 is a potent inhibitor of NF-κB signaling pathways. Ma and colleagues identify distinct roles for A20 ubiquitin-binding ZF4 and ZF7 domains, which exhibit different phenotypes upon mutation, but play synergistic roles in regulating inflammatory responses.
Monticelli and colleagues analyze primary human CD4+ T cells to interrogate gene expression regulatory pathways that distinguish GM-CSF+ pathogenic programs from noninflammatory programs. They identify the transcriptional repressor BHLHE40 as an enforcer of proinflammatory gene expression by suppressing the NF-κB inhibitor miR-146a and the RNase ZC3H12D.
Busch and colleagues use single-cell and bulk TCR sequencing and structural affinity analyses of CMV-specific T cells to show that the immunodominance of high-affinity T cell clones declines during chronic infection with CMV, likely due to cellular senescence.
The pathobiological validity of mouse models of mycobacteria infection is sometimes questioned. O’Garra and colleagues demonstrate that mice share transcriptomic modules with active human tuberculosis and a characteristic type I IFN signature.
van Loo and colleagues provide insights into the action of the anti-inflammatory protein A20. The ZnF7 and ZnF4 ubiquitin-binding domains of A20 are both required to suppress inflammatory signaling and cell death; however, these zinc fingers operate via distinct mechanisms.
Unanue and colleagues examine the immunopeptidome of pancreatic islets in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, to reveal the key features of a restricted component in the self-MHC-II peptidome that causes autoreactivity.
PD-L1 on tumor cells exerts an important dampening effect on T cells via their expression of PD-1. Miller and colleagues find that PD-L1 ‘back-signaling’ into T cells and macrophages can also dampen immune responses within the tumor microenvironment.
Mucosal-associated invariant T (MAIT) cells recognize vitamin B metabolites presented by the molecule MR1. Rossjohn and colleagues generate multiple altered metabolite ligands and determine their structures in the context of MR1 and the TCR to develop a generalized framework for MAIT cell antigen recognition.
The gut microbiota and their proximate immune cells engage in a dialog of reciprocal regulation. James and colleagues describe how immune cell and microbiotal populations vary along the length of the human colon.
Germinal center B cells can undergo rapid proliferation. Shlomchik and colleagues show that germinal center B cells, unlike other rapidly proliferating cells, do not depend on glycolysis, but rather increase their peroxisome content and rewire their cellular metabolism to exclusively utilize fatty acid oxidation for their energetic needs.
HIV-1 infection is associated with persistent inflammation that can contribute to a variety of comorbidities. Luban and colleagues demonstrate that HIV-1 infection results in permanent depletion of innate lymphoid cells, leading to breakdown of gut barrier function and a feed-forward inflammation loop, which includes skewing of NK cells toward an inflammatory/memory phenotype.
Tumor environments are highly acidic due to high concentrations of lactic acid. Ho and colleagues report that tumor-infiltrating regulatory T cells adapt to this tumor environment by upregulating expression of CD36, which allows them to use fatty acids to fuel their metabolism.
Iannacone and colleagues show that the spatiotemporal regulation of type I interferon expression shapes the differentiation of antiviral CD4+ T cells into TFH or TH1 cells.