The discovery of a small molecule inhibitor that targets the inflammasome sensor NLRP3 offers a new path for the development of selective inflammasome blockers with potential therapeutic benefit in a wide range of human diseases (in this issue, see Jiang et al.).
Montagne et al. examine the role of blood–brain barrier (BBB) dysfunction in Alzheimer’s neurodegeneration and how targeting the BBB can influence the course of neurological disorder in transgenic models with human APP, PSEN1 and TAU mutations, APOE4 (major genetic risk), and pericyte degeneration causing loss of BBB integrity.
Brief Definitive Report
RIPK1 regulates cytokine signaling and cell death during infection and inflammation. Peterson et al. show that RIPK1 kinase activity triggers apoptosis in response to bacterial pathogen blockade of innate immune signaling and that this pathway of effector-triggered immunity is critical for a successful antibacterial response.
The thymus medulla prevents T cell–driven autoimmunity via central tolerance. Cosway et al. show that this specialization occurs independently of the topology that classically defines its structure and demonstrate that medulla function requires LTβR-mediated regulation of dendritic cells for negative selection.
Promyelocytic leukemia (PML) nuclear bodies modulate several processes, including senescence or apoptosis. Niwa-Kawakita et al. demonstrate that PML regulates reactive oxygen species (ROS) homeostasis in vivo by coupling ROS to p53 signaling to enforce basal ROS protection and mediate their acute toxicity.
Arkatkar et al. report that B cell–derived IL-6 is critical for T follicular helper cell differentiation, spontaneous germinal center formation, and class-switched autoantibody production during humoral autoimmunity.
Jiang et al. identify a selective and direct small-molecule inhibitor for NLRP3 and provide solid evidence showing that NLRP3 can be targeted in vivo to combat inflammasome-driven diseases.
Role of HIV-specific CD8+ T cells in pediatric HIV cure strategies after widespread early viral escape
A major obstacle to an HIV cure in adult infection is a viral reservoir largely composed of CTL escape mutants. Leitman et al. demonstrate that in children, but not adults, escape variant–specific CTLs are generated that can successfully “corner” the virus.
HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections
Sun et al. show that host cell factor C2 (HCFC2) is necessary for basal and induced Tlr3 transcription; deficiency of HCFC2 compromises survival during influenza virus and herpes simplex virus 1 infections in mice.
Warner et al. show that knock-in mice expressing a human disease–associated STING mutation spontaneously develop inflammatory lung and skin disease, hypercytokinemia, and T cell cytopenia, which occurs independently of IRF3.
Myocardial infarction elicits massive recruitment of monocytes and neutrophils to the myocardium, but the mechanisms that control these processes are not fully understood. Here, Anzai et al. show that GM-CSF is a powerful orchestrator contributing to monocyte and neutrophil production, recruitment, and function.
T cell–mediated inflammation is associated with heart failure, but how heart-infiltrated T cells impact cardiac function remains unknown. Nevers et al. demonstrate that IFN-γ–producing T helper cells interact with cardiac fibroblasts to mediate cardiac fibrosis and dysfunction.
Loss of Krit1 disables an angiogenic checkpoint by reducing TSP1 expression, thereby enabling cerebral cavernous malformation (CCM) formation. Lopez-Ramirez et al. propose that replacing TSP1 by TSP1 fragments or angiogenesis inhibitors may provide an approach to inhibit CCM development.
The first wave of T lymphopoiesis in zebrafish arises from aorta endothelium independent of hematopoietic stem cells
Tian et al. demonstrate that, in addition to giving rise to hematopoietic stem cells, the ventral endothelium of aorta in zebrafish also directly converts to non–hematopoietic stem cell hematopoietic precursors capable of generating a transient wave of CD4 Tαβ lymphocytes.
Martín-Gayo et al. report that human early thymic progenitors can undergo a GATA2-dependent myeloid developmental program leading to resident dendritic cells (DCs) upon JAG1-Notch activation. The identification of JAG1+ DC-permissive intrathymic niches validates the human thymus as a DC-poietic organ.
Th17 cells mediate inflammation and autoimmunity. Although it was known that cytokine IL-2 inhibits Th17 cell differentiation, how it does so was elusive. Using IL-17–specific PTEN-deficient mice, Kim et al. show that phosphatase PTEN inhibits IL-2 production and thus promotes Th17 cell differentiation.
Rezende et al. report that the transplant of 5-lipoxygenase (5-LO)−deficient leukocytes protects mice from GVHD. Treatment with the 5-LO inhibitor zileuton or a LTB4 antagonist at the initial phase of the transplant achieves similar protective effects. 5-LO is a crucial contributor to tissue damage in GVHD.
Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity
Chen et al. demonstrate that human MHC selects a larger human TCR repertoire than mouse MHC. They show how humans optimized TCR diversity and suggest that CDR3 length adjusts for different V segment–MHC affinity.
The molecular mechanism governing affinity-based B cell selection for germinal center colonization is unclear. Zaretsky et al. show that B cell ICAMs promote efficient B cell selection for clonal expansion by supporting sustained interactions with T follicular helper cells.
Technical Advances and Resources
A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis
The etiology of autoinflammation in systemic juvenile idiopathic arthritis is unclear. Cepika et al. use integrated analysis of multidimensional blood stimulation data, applied to patients while off treatment and in complete remission, to reveal underlying cellular and molecular mechanisms that might predispose to disease.