Brief Definitive Report
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.
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.
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.
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.
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.
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.
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 (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.
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.
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.
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.
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.