In concomitance with the JEM 125th anniversary celebration, Jeffrey Ravetch and Falk Nimmerjahn discuss the identification of subclasses within the immunoglobulin G (IgG) isotype by Grey and Kunkel in 1964 and the relevance of these findings for the study of antibody-mediated immune responses.
Internalization of Plasmodium falciparum–infected erythrocytes by brain endothelial cells potentially contributes to cerebral malaria.
SLAM family receptors are involved in humoral immune regulation. In this issue of JEM, Zhong et al. provide evidence that these receptors collectively suppress germinal center reaction but promote production of antigen-specific antibodies.
Brief Definitive Reports
Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients
This work shows that inflammasomes are activated in response to SARS-CoV-2 infection in vitro and in COVID-19 patients. Activation of inflammasomes in moderate and severe cases of COVID-19 contributes to the exacerbated inflammatory response, impacting disease progression and clinical outcome.
The naive polyclonal CD4 T cell repertoire can differentiate into multiple lineages during acute viral infection, with some clones exhibiting a preferred lineage choice, as revealed by scRNA-seq and scTCR-seq. TCR motifs can partially skew clone-intrinsic lineage preferences toward the TFH fate.
Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects
SLP76 is a key molecule involved in the T cell signaling pathway; therefore, SLP76 deficiency can lead to a severe type of immunodeficiency. By reporting on a patient with germline mutation in SLP76, deficiency in this gene is linked, for the first time, to a human disease.
The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function
The m6A reader YTHDF2 is a novel regulator of inflammatory pathways in HSCs. YTHDF2 loss upregulates m6A-modified proinflammatory transcripts, resulting in chronic HSC inflammatory activation, myeloid bias, and functional exhaustion.
Kuribayashi et al. demonstrate that the engraftment of aged hematopoietic stem cells into intact young niche largely rejuvenates their transcriptional profile but does not restore their function, highlighting a key role for age-associated cell-intrinsic defects in HSC aging.
Elongated neutrophil-derived structures are blood-borne microparticles formed by rolling neutrophils during sepsis
During bacterial sepsis, tethers break off from neutrophils rolling on the vessel wall, destabilizing neutrophil rolling and forming elongated neutrophil-derived structures (ENDS) in the blood circulation. ENDS are phosphatidylserine- and tetraspanin-negative structures that fragment, round up, and release S100-A8/A9 upon degradation.
Suppression of local type I interferon by gut microbiota–derived butyrate impairs antitumor effects of ionizing radiation
Mechanisms by which specific gut microbiota affect cancer therapies by modulating the antitumor immune response is under intensive investigation. This study reveals selective targeting of butyrate-producing microbiota may provide a therapeutic option to enhance radiotherapy.
SPRED1 is a negative regulator of the MAPK pathway frequently deleted in human melanoma. Through in vivo modeling in zebrafish and mechanistic analyses in human cell lines, Ablain et al. demonstrate that SPRED1 inactivation confers resistance to targeted inhibition of V600 mutant BRAF, the most common driver of melanoma.
This study demonstrates how gene expression profiles of white blood cells in acute spinal cord injury patients can be utilized for the diagnosis of the injury severity and the neurological level of injury.
Technical Advances and Resources
Huang et al. report an integrated, robust CRISPR genome editing platform for natural killer (NK) cells that combines the advantages of feeder-free ex vivo expansion and Cas9 RNP nucleofection to replace inefficient plasmid transfection and viral transduction, which have long hindered the advance of NK cell research.
Antibody potency, effector function, and combinations in protection and therapy for SARS-CoV-2 infection in vivo
Human monoclonal antibody potency in vitro does not uniformly correlate with its in vivo neutralization of SARS-CoV-2. Antibody Fc-effector function is important for in vivo neutralization, and antibody combinations show superior efficacy compared with single antibodies.
Neurological symptoms are frequently observed in COVID-19. Here, we examine the neuroinvasive potential of SARS-CoV-2 and demonstrate infection of neurons in three separate approaches: mouse model, human brain organoid, and autopsy of COVID-19 patients.
Plasmodium falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood–brain barrier in cerebral malaria
Plasmodium falciparum parasites causing cerebral malaria express specific PfEMP1 proteins (group A+CM) on infected erythrocytes. Group A+CM PfEMP1s allow entry into brain microvascular endothelial cells; this causes cell swelling and drives cerebral malaria pathology by disrupting the blood–brain barrier.
SLAM family receptors control pro-survival effectors in germinal center B cells to promote humoral immunity
Zhong et al. show that the SLAM family of receptors is critical for T cell–dependent humoral immunity due to its ability to enhance expression of pro-survival effectors such as Bcl-2 and BCR in germinal center B cells.
Seasonal influenza virus infections cause severe illness and a substantial number of deaths worldwide every year. This study reveals that the CD4+ follicular regulatory T cells are necessary for optimal antigen-specific humoral immunity following influenza virus challenge.
The role of Fas in germinal center (GC) homeostasis is controversial. Razzaghi et al. show that Fas is a strong cell-intrinsic regulator of the GC and that its loss defines an aggressive subtype of GC-derived lymphoma.
The cells that support hematopoietic stem cells in the developing liver in vivo are unknown. Systematic genetic dissection in vivo identifies endothelial and hepatic stellate cells as the major functional source of a key hematopoietic stem cell maintenance factor, stem cell factor (SCF).
Loss of Elp3, the catalytic subunit of the tRNA modifying complex Elongator, activates a p53-dependent antitumor checkpoint, leading to the death of committing hematopoietic progenitors in mice. Bypass of this checkpoint through p53 gene deletion or spontaneous mutation promotes leukemia/lymphoma.
Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes
Kim and colleagues show that OCA-B in T cells is essential for the generation of type 1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.
Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
Adipose-specific deletion of mitochondrial redox Trx2 induces excessive mitophagy in white adipose tissue with increased inflammation and increased lipolysis, promoting hepatic glucose production and development of T2DM with hepatic steatosis. Administration of NF-κB inhibitor prevents adipose mitophagy and ameliorates T2DM progression.
Efficient homing of antibody-secreting cells to the bone marrow requires RNA-binding protein ZFP36L1
Splenic ASCs generated late in the immune response display increased surface abundance of CXCR4 and of the integrins α4 and β1. ZFP36L1 controls the range of integrin expression, facilitating transition of ASCs to their survival niche in the bone marrow.
Apelt et al. identify patients with inherited ERCC1 mutations that impede DNA damage repair through protein instability and reduced recruitment to DNA repair machineries. Together, this results in a phenotype comprising short stature, photosensitivity, and severe liver and kidney impairment.
Juvenile arthritis represents the most common rheumatic manifestation in children. LACC1 deficiency has been identified as a monogenic cause of juvenile arthritis. In this issue, Omarjee et al. demonstrate a new role of LACC1 in autophagy and metabolism in macrophages.
NK cells are able to upregulate SIRPα, which transmits a strong inhibitory signal upon CD47 engagement. Modulation of this immune checkpoint can enable the generation of universal allogeneic regenerative cell products or enhance NK cell–mediated tumor cell killing.
DNA methylation plays a critical role in innate immune response, but the underlying mechanisms have not been clarified. The authors found a single-nucleotide methylation controls IFN-I induction and antiviral immunity via regulating IRF3 recruitment both in human and mouse.