People & Ideas
Matthew Krummel and colleagues discuss the positive trends and initiatives that emerged among scientists during the COVID-19 lockdown.
Brief Definitive Reports
How memory Th2 cell subsets orchestrate allergic airway inflammation remains unclear. Rahimi et al. demonstrate that tissue-resident and circulating memory Th2 cells are functionally and transcriptionally distinct subsets with unique roles in promoting allergic airway disease.
Pallett et al. identify mononuclear phagocyte and T cell subsets able to reside in the human liver for over a decade, probing their retention and replenishment using HLA-mismatched allografts and hepatic venous sampling.
The mechanisms that regulate V(D)J recombination to ensure antigen receptor allelic exclusion are poorly understood. The authors show that poor quality Vβ recombination signal sequences stochastically restrict the incidence of Vβ rearrangements to enforce TCRβ allelic exclusion.
Pancreatic ductal adenocarcinoma (PDAC) cells rely heavily on glutamine metabolism. Recouvreux et al. demonstrate that nutrient stress caused by glutamine deprivation drives epithelial-mesenchymal transition (EMT) and aggressive behaviors in PDAC cells through up-regulation of the EMT master regulator Slug.
Uncovering mechanisms that drive pancreatic cancer could lead to effective therapies for this lethal disease. This study reveals how pancreatic cancer cells hyperactivate a pathway to sustain their proliferation. Inhibiting this pathway affects cancer cells, but not normal cells, highlighting a new therapeutic opportunity.
Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial
A CpG-stimulated autologous tumor cell vaccine for patients with MCL is safe and feasible and induces detectable antitumor T cell immune responses. Patients who received the CpG-MCL vaccination demonstrated freedom from MRD at 1 yr after ASCT that surpassed previously reported rates.
BACH2 drives quiescence and maintenance of resting Treg cells to promote homeostasis and cancer immunosuppression
BACH2 is repurposed following Treg lineage commitment to promote the functional quiescence and long-term maintenance of rTreg cells by restraining TCR-driven aTreg differentiation programs. This function is required for immune homeostasis and durable immunosuppressive responses in cancer.
The C-type lectin layilin has been observed in several human cancers, but its function on immune cells is unknown. This study demonstrates that layilin is highly expressed on clonally expanded CD8+ T cells in human melanoma and augments integrin-mediated cellular adhesion to enhance antitumor immunity.
Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation
This manuscript presents a comprehensive epigenomic analysis of human thymocyte development and provides new molecular insights into the mechanism by which the TCRA enhancer is activated during thymic maturation by developmentally programmed repression of HOXA factors.
IL-33 promotes anemia during chronic inflammation by inhibiting differentiation of erythroid progenitors
Erythroid progenitors preferentially express ST2, the receptor for IL-33; this cytokine is necessary and sufficient to cause anemia during chronic inflammation. IL-33 directly inhibits differentiation of erythroid progenitors by activating NF-κB signaling, which is normally downregulated in erythropoiesis.
Whether proplatelet formation alone can explain physiological platelet production is unclear. Large-scale in situ analysis reveals that megakaryocytes undergo platelet biogenesis via membrane budding. Mathematically, membrane budding provides a robust explanation for how the physiological adult platelet biomass is maintained.
While glomerulosclerosis commonly progresses to kidney failure, its mechanisms are unclear. Using murine models and human samples, the authors show that progressive glomerulosclerosis results from loss of decay-accelerating factor (DAF/CD55) on podocytes, which in turn initiates complement C3aR signaling and downstream IL-1β/IL-1R1–mediated podocyte injury and loss.
Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model
Wang et al. demonstrate that a mAb specific for the human microglial receptor TREM2 induces microglia proliferation, ameliorates Aβ-induced pathology in a mouse model of Alzheimer’s disease, and can be given safely in a first-in-human phase I clinical trial.
Mailhot et al. show that the cytokine IL-1β directly modulates pain in animal models of chronic inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and osteoarthritis through a novel subclass of IL-1R1+ nociceptors.
Staphylococcus aureus secretes pore-forming leukocidins that kill leukocytes as part of the bacterium’s evasion strategy. Leukocidin-based vaccination results in toxin-neutralizing antibodies and toxin-specific CD4 lymphocytes that block the toxins and boost host-mediated antimicrobial responses to protect mice from bloodstream infection.
Lee et al. show that circulating NS1 protein does not contribute to dengue pathogenesis in mice infected with highly virulent DENV2 strains. Instead, structural prME region is found to play a critical role in the in vivo fitness and virulence of these strains.
Japanese encephalitis virus–primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis
Chen et al. show that Japanese encephalitis virus (JEV)–elicited CD8+ T cells and antibodies play protective and pathogenic roles in Zika virus–infected wild-type C57BL/6 mice, respectively, and JEV-elicited CD8+ T cells abrogate anti-JEV antibody–mediated enhancement of Zika virus infection in mice.