ON THE COVER
Yan et al. describe the role of TIPE2 in the polarization of myeloid-derived suppressor cells during tumorigenesis. The cover shows the multiplexed fluorescence immunohistochemistry of a human lung cancer tissue array, in which tumor tissue and adjacent tissue from the same patient are compared. Image © Yan et al., 2019. See https://doi.org/10.1084/jem.20182005.
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People & Ideas
Using a single-cell RNA-seq approach, the work by Wang et al. establishes an atlas of human colon, rectum, and ileum epithelial cells. Their study reveals that different regions have specialized nutrient absorption preferences, microbe defenses, and endocrine function. They also identify new markers for a variety of cell types.
Upon leukemic transformation, extensive remodeling of the bone marrow microenvironment results in altered cellular and biochemical interactions promoting tumor cell development and survival or reducing treatment responsiveness. Therapeutic targeting of the “malignant” leukemic niche may treat or mitigate disease relapse.
In this review, we dissect the role of galectins in shaping cellular circuitries governing each hallmark of tumors, illustrating relevant examples and highlighting novel opportunities for treating human cancer.
This review describes how gene therapy of severe combined immunodeficiency became a reality, primarily based on the expected selective advantage conferred by transduction of hematopoietic progenitor cells. Thus, it resulted in a progressive extension to the treatment of other primary immunodeficiencies.
Brief Definitive Reports
The pathogenesis of glial tau pathology is unknown. This study shows glial tau pathology can propagate in the absence of neuronal tau. In particular, oligodendrocytes transmit tau pathology via their own processes, independent of neuronal tau.
Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Du et al. describe unexpected roles of mevalonate metabolism–fueled protein geranylgeranylation, but not farnesylation, in driving thymocyte egress through modulating Cdc42 and Pak activities.
Arroyo and Pepper demonstrate that interactions with B cells, not dendritic cells, are required for the priming of the CD4+ T cell response during Plasmodium infection. This results in a Tfh-biased response as reported by others in both mice and humans.
This study shows that the regulatory innate lymphoid cell (ILCreg), a recently described IL-10–producing innate lymphocyte, is not present in mice bred in four different facilities. Instead, group 2 ILCs provide an inducible source of IL-10 in the intestine.
Technical Advances and Resources
Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine
Single-cell transcriptome analysis of epithelial cells from human ileum, colon, and rectum reveals different nutrient-absorption preferences in the small and large intestine, providing a rich resource for further characterization of human intestine cell constitution and functions.
Mechanism of differential Zika and dengue virus neutralization by a public antibody lineage targeting the DIII lateral ridge
Evaluation of the human antibody response to Zika virus has identified common germline-derived mAbs capable of cross flavivirus neutralization. Zhao et al. provide a detailed mechanistic understanding of how flavivirus infections are prevented in a strain-specific manner by a representative mAb.
HIV-1 is an exceptionally difficult vaccine target, and only certain types of antibodies are effective. Vaccination induces antibodies that bind the virus with different efficiencies. This study investigates this process and reveals how the immune system works to improve the binding capacity of each antibody.
In patients, gain-of-function (GOF) mutations in PIK3CD break tolerance, causing highly penetrant secretion of autoreactive IgM. Mouse models reveal that Pik3cd GOF subverts the response to self-antigen, preventing the induction of anergy and instead stimulating plasmablast and GC formation.
This study sheds light on the mechanism by which autoantibodies to transglutaminase 2 (TG2) are formed in celiac disease. The authors find that there is no deletion or silencing of autoreactive TG2-specific B cells and that production of anti-TG2 autoantibodies is controlled by T cell help.
Cytokines and lipid mediators are key regulators of inflammation; but how they are mechanistically linked is poorly understood. Here, Mukhopadhyay et al. show a novel regulation between cytokine IL-10 and lipid mediator PGE2 that functionally connects them to intestinal inflammation.
A super enhancer termed DR/DQ-SE within the MHC-II locus was examined by CRISPR mutagenesis. DR/DQ-SE was found to regulate HLA-DRB1, -DQA1, and -DQB1 gene expression by controlling chromatin interactions/looping between MHC-II gene promoters and CTCF binding elements.
Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis
Xiong et al. show that CCP3 performs deglutamylation of BAP1 to stabilize BAP1, which eliminates H2AK119Ub from Hoxa1 promoter and initiates Hoxa1 expression, leading to enhanced HSC self-renewal.
TIPE2 specifies the functional polarization of myeloid-derived suppressor cells during tumorigenesis
In this study, Yan et al. demonstrate that TIPE2, which is induced by tumor-derived ROS, promotes the functional polarization of protumoral myeloid-derived suppressor cells (MDSCs) during tumorigenesis by specifying the expression of MDSC signature genes such as Cebpb.
As a novel type of anticancer reagent, imatinib inhibits not only BCR-ABL oncogenic protein but also LCK in T cells as an off-target, being able to selectively deplete mature T reg cells and thereby evoke effective immune responses to various cancers.
This study implicates the key regulator of alternative polyadenylation, CFIm25 in dermal fibrosis and in systemic sclerosis (scleroderma) pathogenesis. CFIm25 downregulation promotes the expression of profibrotic factors, exaggerates bleomycin-induced skin fibrosis, while CFIm25 restoration attenuates skin fibrosis.
Using mice modelling patients’ variant, this study demonstrates that a homozygous DNAH17 missense variant causes asthenozoospermia and specifically destabilizes microtubule doublets 4–7 in flagella, which could be largely due to the storage of sperm in epididymis.