February 2017 | Volume 214, No. 2
Brief Definitive Reports
- Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury
Immune responses to central nervous system (CNS) injuries are multifaceted, but their contributions are incompletely understood. Here, Gadani et al. describe type 2 innate lymphocytes as novel meningeal-resident cells, characterizing their transcriptional profile and response to CNS injury.
- CNS-targeted autoimmunity leads to increased influenza mortality in mice
Glenn et al. show that EAE induction impairs influenza immune responses, worsens influenza pathology, and is marked by early EAE-induced recruitment of suppressive myeloid cells to the lungs.
- Antibody-secreting plasma cells persist for decades in human intestine
This study provides a definite answer to the long-standing question concerning the longevity of the secretory antibody response. Landsverk et al. show that antigenic attrition affects a minor plasma cell subset and that distinct plasma cells are likely maintained for life in the human small intestine.
- Class II MHC–independent suppressive adhesion of dendritic cells by regulatory T cells in vivo
Yan et al. demonstrate that in vivo T reg cells can form prolonged contacts with dendritic cells (DCs) in an MHC-independent manner and suppress the ability of the same DCs to contemporaneously engage in stable interactions with and activate conventional T cells.
- Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy
Chen et al. show that regulatory T cells adhere to dendritic cells (DCs) with high binding forces. This strong binding causes cytoskeletal polarization in the latter, which limits DCs’s ability to form productive engagement with other antigen-specific T cells.
- The epidermal polarity protein Par3 is a non–cell autonomous suppressor of malignant melanoma
Mescher et al. uncover a novel tissue-borne tumor suppression mechanism, engaging polarity proteins in the epithelial microenvironment that prevent malignant outgrowth of neighboring cell types through control of heterologous cell–cell contacts. Moreover, their data support an emerging role of P-cadherin, which is frequently amplified in human carcinoma, as a protumorigenic and proinvasive adhesion molecule, thus placing it as a promising druggable target to disrupt tumor–microenvironment interactions for anticancer therapy.
- CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia
Riether et al. show that CD70/CD27 signaling activates stem cell gene expression programs in acute myeloid leukemia (AML). Blocking the CD70/CD27 interaction inhibits self-renewal and induces differentiation of AML blasts and stem/progenitor cells.
- The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment
Williams et al. show that 4-BB and LAG-3, previously identified as EGR2 targets from in vitro T cell anergy studies, are sufficient to identify dysfunctional tumor antigen–specific CD8+ T cells in the tumor microenvironment. These markers facilitated detailed transcriptional and phenotypic characterization and provided therapeutic targets for tumor control.
- Defective ATG16L1-mediated removal of IRE1α drives Crohn’s disease–like ileitis
Tschurtschenthaler et al. report a Crohn’s disease–like ileitis mediated by IRE1α that develops in mice with intestinal-epithelial Atg16l1 deletion when they age. The authors propose a selective autophagy process involved in the removal of IRE1α clusters during ER stress.
- IKKα controls ATG16L1 degradation to prevent ER stress during inflammation
Decreased ATG16L1 stabilization is associated with increased susceptibility to develop inflammatory bowel diseases. Diamanti et al. identify IKKα as a central upstream kinase of ATG16L1, providing evidence that ATG16L1 stabilization is controlled by phosphorylation downstream of TNF and NOD activation.
- Peptidylarginine deiminase 4 promotes age-related organ fibrosis
Peptidylarginine deiminase 4 (PAD4) citrullinates proteins. In neutrophils, it causes chromatin decondensation and release of NETs, which are injurious. Martinod et al. show in this study that NETs promote fibrosis in a cardiac model and that PAD4-deficient mice have reduced age-related organ fibrosis.
- TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity
Lang et al. identify E3 ligase TRIM65 as an essential component for the MDA-5 signaling pathway and provide solid evidence showing the importance of ubiquitination in MDA5 oligomerization and activation.
- Dissection of SAP-dependent and SAP-independent SLAM family signaling in NKT cell development and humoral immunity
Chen et al. dissect SAP-dependent and SAP-independent SLAM family signaling in the regulation of NKT cell development and follicular T helper cell differentiation using a novel mouse model lacking all seven SLAM family receptors.
- Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival
Natural killer (NK) cells eradicate virus-infected and transformed cells. Viant and colleagues describe the hierarchy of survival proteins and their apoptotic partners that govern NK cell survival. These data will inform approaches to harness NK cell activities in immunotherapies.
- Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation
Lordén et al. show that the phosphatidic acid phosphatase lipin-2 is a key regulator of the cellular machinery that generates IL-1β in macrophages. This work provides a molecular explanation for the development of the autoinflammatory disease known as Majeed syndrome.
- 5-hydroxytryptamine synthesized in the aorta-gonad-mesonephros regulates hematopoietic stem and progenitor cell survival
Lv et al. show that in mice, 5-HT can be synthesized in the aorta-gonad-mesonephros and acts as a novel endogenous regulator of hematopoietic stem and progenitor cell (HSPC) development. The promoting effect of 5-HT on the survival of HSPCs in the intraaortic hematopoietic cluster is mediated through Htr5a-AKT-Foxo1 signaling.
- Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy
Sha et al. report that Hsp90β, which is up-regulated in astrocytes of human epileptogenic tissue, interacts with GLT-1 and recruits it to 20S proteasome for degradation. The Hsp90 inhibitor 17AAG exhibits beneficial effects in a model of temporal lobe epilepsy.