People & Ideas
Ruth Scherz-Shouval is an Assistant Professor in the Department of Biomolecular Sciences at the Weizmann Institute of Science, Israel. Her lab is interested in the tumor microenvironment (TME), how stress responses can shape the TME, and also how different cells within the TME interact.
Not only macrophages, but also neutrophils, are a main target of clodronate. In this issue of JEM, Culemann et al. demonstrate that anti-inflammatory effects of clodronate liposomes are driven via stunning of polymorphonuclear neutrophils and not solely through depletion of macrophages.
DNASE1 (D1) and DNASE1L3 (D1L3) synergistically reduce the severity of systemic infections caused by Staphylococcus aureus. In this issue of JEM, Lacey et al. developed D1−/−, D1L3−/−, and D1−/−D1L3−/− mice to show that exogenous addition of the DNase formulation Dornase alfa could facilitate removal of biofilms.
Harker and Lloyd review the multifaceted roles of Th2 cells in human asthma, highlighting their influence of tissue location and disease severity. They also explore how Th2 cells and their cytokines have been targeted for biologic therapies for asthma patients.
Brief Definitive Reports
The authors show that the anti-inflammatory effects of clodronate liposomes do not result from the depletion of mononuclear phagocytes but from a functional stunning of polymorphonuclear neutrophils. These findings necessitate a critical revision of the current literature on the role of monocytes and macrophages in inflammation.
Both DCs and monocytes capture antigen for presentation to lymph node T cells. Here, Rawat et al. show that DCs use the chemokine receptor CCR7, while monocytes follow chemokines secreted by migratory DCs to reach the nodes and control immunity.
The mechanism of Ca2+ release from ER in resting cells was unclear. Liu et al. demonstrate that VMP1 is required for ER Ca2+ release in resting cells, and VMP1 deficiency in T cells leads to ER Ca2+ overload and massive apoptosis.
Technical Advances and Resources
Spatial mapping reveals granuloma diversity and histopathological superstructure in human tuberculosis
Sawyer et al. reveal the diversity of human tuberculosis granulomas by profiling 726 individual lesions by multiplex imaging. As well as necrotizing lesions, they identify four distinct lesion types that organize in a histopathological superstructure around necrotic granulomas.
Extracellular nucleases of the DNASE1 family are conserved in vertebrates, yet their physiological function remains unclear. This study shows that DNASE1 and its homolog DNASE1L3 jointly facilitate resistance to systemic infection with Staphylococcus aureus by digesting bacterial biofilms.
IEC-intrinsic IL-1R signaling holds dual roles in regulating intestinal homeostasis and inflammation
This study characterizes the dual role of IL-1R signaling in IECs during C. rodentium infection and DSS-induced colitis. IEC-intrinsic IL-1R signaling enhances IL-22–induced AMPs for protection but contributes to damage-induced inflammation through induction of chemokines and ROS genes.
Stromal and therapy-induced macrophage proliferation promotes PDAC progression and susceptibility to innate immunotherapy
Stromal desmoplasia drives local proliferation of TAMs and induces their immunosuppressive ability through altering p21 expression. These changes in p21 in TAMs also potentially render tumors more sensitive to CD40 agonist therapy.
Tracking phagocytic tumor-associated myeloid cells in a novel autochthonous lung tumor model reveals key responses to neoplastic cell engulfment, including elevated oxidative phosphorylation and immune suppression. The phagocytic signature is also enriched in myeloid cells from human tumors.
Abdulla et al. show that the LMO2 transcription factor, a key driver of human T-lymphoblastic leukemia, inhibits thymocyte competition in a transgenic mouse model and that this enables LMO2 to promote T-lymphoblastic leukemia.
Billiet et al. identify the post-thymic progeny of the agonist-selected CD10+ PD-1+ precursors in humans based on shared characteristics of the T cell receptor repertoire and the transcriptome. This lineage represents a well-defined but heterogeneous, unconventional TCRαβ+ lineage mostly confined within the CD8+ Helios+ T cells.
Detailed analysis of patients with APDS2 and a novel mouse model of Pik3r1 LOF reveals multiple cellular defects, some of which are unique to APDS2 and not seen in APDS1. This is associated with unique signaling changes caused by Pik3r1 LOF.
A neomorphic mutation in the interferon activation domain of IRF4 causes a dominant primary immunodeficiency
Thouenon et al. describe a novel primary immunodeficiency associated with defective plasma cell differentiation. They reveal that an amino acid exchange located within the interferon activation domain of IRF4 downregulates transcription on ISRE sites because of altered protein interaction.