BRD4 is a bromodomain-containing protein that binds acetylated histones to regulate transcription. In this issue of JEM, Milner et al. show that BRD4 plays a critical role in the effector function of CD8 T cells responding to infection and cancer.
Extracellular vesicle– and particle-mediated communication shapes innate and adaptive immune responses
While tumor-derived extracellular vesicles and particles (EVPs) are well characterized, little is known about the cargo and function of immune cell–derived EVPs. Here, we review the functional roles of immune cell–derived EVPs in normal physiology and disease.
Pruner and Pepper provide a timely literature review detailing the critical, heterogenous functions of lung resident CD4 memory T cells during respiratory viral infection. Implications for vaccine design and protection from heterologous influenza and SARS-CoV-2 reinfection are discussed.
Brief Definitive Reports
Milner et al. reveal the chromatin reader BRD4 controls the differentiation and maintenance of a terminally differentiated CD8 T cell state. This study provides molecular insights into the manipulation of T cell differentiation for improved protection from infection and malignancy.
Human STAT3 gain-of-function (GOF) mutations are linked to type 1 diabetes (T1D). This study establishes a STAT3-GOF mouse model that recapitulates the human T1D phenotype. STAT3-GOF drives cytotoxic CD8+ T cells that are resistant to terminal exhaustion, epigenetically distinct, and sufficient to accelerate T1D development.
Chronic T cell proliferation in brains after stroke could interfere with the efficacy of immunotherapies
Heindl et al. describe the local proliferation and clustering of T cells in the brain of mice and humans after stroke. This previously unrecognized phenomenon could explain why blocking cerebral leukocyte invasion might fail to improve long-term stroke recovery.
In this paper, we evaluate whether elimination or repopulation of microglia affects Aβ-induced tau seeding and spreading. Elimination of microglia increases NP-tau seeding and spreading. Interestingly, repopulated microglia cluster around amyloid plaques, exhibit a homeostatic gene expression signature, and also result in elevated NP-tau seeding and spreading.
VISTA biology has yet to be fully resolved despite much enthusiasm to define it as an immune checkpoint protein. Here, we show that VISTA antibodies can singly activate human monocytes and provide evidence that Syndecan-2 can regulate VISTA interactions.
We show that the Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) family proteins SERCA2 and SERCA3 have redundant functions that are required for RAG gene expression and DNA breaks during V(D)J recombination. Loss of SERCA activity leads to B lymphopenia in mice and humans.
Technical Advances and Resources
Single-cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord
This study uses single-cell RNA sequencing to investigate the transcriptional heterogeneity of all cell types known to comprise the acutely injured spinal cord in mice. The authors investigate both cell subtype heterogeneity and potential signaling interactions between myeloid, vascular, and macroglia cells.
Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19
Single-cell profiling demonstrates multifarious dysregulation of innate immune phenotype associated with COVID-19 severity. Severe COVID-19 is associated with hyperactivation of neutrophils and NK cells, while monocytes take on tolerogenic phenotypes. Meanwhile, mild COVID-19 is associated with limited, or rapidly resolved, immune perturbation.
Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics
SARS-CoV-2 replication in the upper respiratory tract initiates infection and leads to viral transmission. Cheemarla et al. show that a dynamic innate immune response can curtail viral replication early in infection, and that recent exposure to rhinovirus accelerates innate defenses and blocks viral replication.
Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) are heterozygous for rare STAT3 variants. The mechanism of dominance was recently questioned. The authors show that both in-frame and out-of-frame STAT3 variants underlie AD-HIES by negative dominance and not haploinsufficiency.
This study describes the multiple facets and molecular basis of excessive Th2 cytokine production by CD4+ αβ T lymphocytes as a possible mechanism underlying persistent upper airway inflammation and blood eosinophilia in a patient with inherited complete T-bet deficiency.
Repression of Spi1 encoding PU.1 is crucial for early T cell lineage commitment and depends on GATA3 and Runx1. Stage-specific Runx1 and GATA3 binding during commitment identifies a closed intronic site of mouse Spi1 that substantially contributes to Spi1 repression.
Expression of regulatory T cell lineage–specifying factor Foxp3 is governed by distinct cis-regulatory elements of the Foxp3 gene. Systematic analyses indicate that these elements coordinate to maximize regulatory T cell suppressive capacity by enhancing their induction and lineage stability.
Whether and how m6A modifications regulate NK cell immunity remain unknown. Here, Ma et al. show that NK cell proliferation, survival, and effector functions are positively controlled by the RNA m6A reader YTHDF2.
E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non–small cell lung cancer
Recurrent inactivated mutations in central precocious puberty-associated gene MKRN3 lead to lung cancer proliferation and progression through PABPC1 ubiquitination–mediated global protein synthesis. MKRN3 is a bona fide tumor suppressor, and MKRN3-PABPC1 deregulation represents a key pathway in NSCLC oncogenesis.
GSAP plays an important role in Alzheimer's disease, but the underlying cellular and molecular pathways remain unclear. Using unbiased multi-omics approaches, this study demonstrates that GSAP regulates lipid homeostasis in mitochondria-associated membranes (MAM), which affects mitochondrial function associated with the disease.
Loss of direct adrenergic innervation after peripheral nerve injury causes lymph node expansion through IFN-γ
This study shows loss of sympathetic innervation to the popliteal lymph node to induce IFN-γ expression in CD8 T cells, causing expansion. This is rescued by β2 adrenergic receptor agonists, demonstrating the pro-inflammatory effect of loss of direct adrenergic input.
We tested the role of endothelial dysfunction in the development of COPD/emphysema. We found that restoration of lung endothelial cells and blockade of endothelial-derived leucine-rich α-2-glycoprotein perturbs the pathogenesis of COPD/emphysema.
Memory B cells comprise a heterogenous group of cells. Viant et al. report on the use of an unbiased lineage-tracking approach to explore the origins and properties of memory B cell subsets in mice with an intact immune system.