As part of the JEM 125th Anniversary Insights, Ingber reviewed how Alexis Carrel's JEM study on the culture of whole organs inspired a series of scientific, engineering, and medical breakthroughs.
In celebration of JEM’s 125th anniversary, Maguin and Marraffini discuss the discovery of DNA as carrier of genetic information by Avery and colleagues in 1944, from the development of the field of molecular biology to the discovery of CRISPR-Cas for gene editing.
To commemorate JEM's 125th anniversary, Kim and Cantor discuss the seminal work by Landsteiner and colleagues on human blood groups and reflect on how those findings have influenced our current understanding of immune recognition, clonal selection, and self-tolerance.
As part of JEM’s 125th anniversary celebration, Olivier Elemento discusses Peyton Rous’s discovery in 1911 that led to the identification of virus-inducing tumors, oncogene discovery, and the development of modern tumor biology.
Kim et al. provide evidence that breathing induces large pH oscillations on the human airway surface, contributing to host defense to bacteria. pH oscillations are impaired in cystic fibrosis with potential implications for bacteria colonization in patients.
A significant number of patients respond poorly to current asthma interventions. Balestrini et al. advance the concept that sensory nerves control inflammation in asthma, demonstrating that a novel inhibitor of TRPA1, a chemical irritant receptor, suppresses asthmatic inflammation in several preclinical species.
Effective and safe treatments for Alzheimer’s disease have been an elusive target for scientists. In this issue of JEM, Rynearson et al. present a beacon of hope for this field with a preclinical evaluation of a potent and robust γ-secretase modulator (GSM).
The activity of individual nuclear receptors is not only determined by specific actions in specific target cells, but also by their regulation in the tissue environment, as exemplified by the role of liver X receptors in regulating T cell development and effector functions.
In this issue, human marginal zone B cell development is tracked from early progenitors to the memory compartment, addressing changes in age and autoimmunity, the sequence of development in the gut-associated lymphoid tissue, and clonal sharing among memory cells.
People & Ideas
Gwendalyn Randolph shares her observations and ideas for how institutions can partner with women to support their careers in STEM.
Tissue-resident memory T cells (TRM) patrol peripheral tissues and mediate a long-term protective immunity. Okła et al. review recent advances in TRM in the context of tumor immunity and immunotherapy.
The architectural design of CD8+ T cell responses in acute and chronic infection: Parallel structures with divergent fates
Chung et al. discuss the architectural design of CD8+ T cell responses during acute and chronic viral infection, emphasizing the parallelism of the differentiation pathways, the heterogeneity of the resultant T cell states, and the underlying transcriptional and epigenetic networks controlling these differentiation processes.
Natural killer cells are critical effectors of antiviral host defense. This review summarizes the recent literature, current paradigms, and molecular mechanisms underlying the ability of these innate lymphocytes to mount adaptive responses against viral infection in humans and mice.
Brief Definitive Reports
Plasmacytoid dendritic cells (pDCs) are not permissive to SARS-CoV-2 infection but, upon viral exposure, differentiate into subsets and rapidly produce type I and III interferons. Mechanistically, pDC activation depends on IRAK4 and UNC93B1 expression.
The nuclear receptor liver X receptor β (LXRβ) is a critical regulator of cholesterol homeostasis in mammalian cells. Here, we report that pan-T cell– and T reg cell–specific LXRβ ablation leads to a survival defect of LXRβ-deficient effector T cells and impaired T reg cell functionality.
By characterizing the poorly defined T cell composition in developing human fetal skin, Reitermaier et al. identify a unique population of TCR αβγδ+ T cells. These cells may contribute to early skin development and immune defense against invading pathogens in utero.
Combining transcriptomic and TCRαβ repertoire analysis of circulating and tumor-infiltrating CD8 T cells from patients with metastatic melanoma, Lucca et al. identify a blood-based population with effector properties that reflect those of clonally related tumor-resident T cells.
Moon et al. report that antigen presentation via MHC II with coreceptor PD-L1 expressed on intestinal epithelial cells is an important contributing factor for the generation of CD4+CD8αα+ intraepithelial lymphocytes.
Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine
Yellow fever virus live attenuated vaccine can rarely cause life-threatening disease. Inherited IFNAR1 deficiency was previously reported in one patient. Here, we report a patient with inherited IFNAR2 deficiency and three other patients with neutralizing auto-antibodies against type I IFNs.
Mutations in the actin-regulatory protein Hem-1 result in primary immunodeficiency disease in humans. Using murine models, Suwankitwat et al. show that myeloid-specific Hem-1 is essential for the development of alveolar macrophages and protection against influenza A virus and Streptococcus pneumoniae.
Krishnan et al. outline a novel pathway of myeloid cell development in healthy gingiva. They identify HSPCs in noninflamed gingiva tissue, which support the generation of a proportion of the innate immune cells that police this barrier site.
Technical Advances and Resources
Zhuang et al. identify SARS-CoV-2–specific T cell epitopes recognized by CD4+ and CD8+ T cells in BALB/c and C57BL/6 mice. SARS-CoV-2–specific T cells are protective and cross-reactive in vivo, and are shaped by type I IFN signaling.
This study identifies a developmental trajectory from human IgMhi gut homing transitional 2 cells to marginal zone B cells, all stages of which are affected in patients with severe systemic lupus erythematosus.
Analysis of classical neutrophils and polymorphonuclear myeloid-derived suppressor cells in cancer patients and tumor-bearing mice
Veglia et al. characterize the heterogeneity of polymorphonuclear neutrophils (PMNs) in the tumor microenvironment, spleen, and peripheral blood. The identification of neutrophil populations with potent immune suppressive activity opens selective targeting opportunities.
We show that SARS-CoV-2 infection elicits broadly reactive and highly functional T cell responses. In addition, recovered individuals show persistent alterations in CD4+ and CD8+ T cell memory compartments 6 months after infection.
Kim et al. show that airway surface liquid has elevated pH during inhalation due to the low CO2 content of room air and the presence of bicarbonate and carbonic anhydrase 12. Breathing-induced alkalinization contributes to host defense and is impaired in cystic fibrosis and perhaps other respiratory diseases.
Balestrini et al. show the identification of a TRPA1 inhibitor that suppresses airway smooth muscle contraction, inflammation, edema, and cough in preclinical models and show target engagement in humans, demonstrating that pharmacologic inhibition of TRPA1 is a promising therapy for asthma.
GSMs preferentially attenuate levels of the aggregation-prone Aβ42 peptide by binding to the γ-secretase enzyme and altering exopeptidase-like processing. Rynearson et al. demonstrate the ability of an advanced-stage GSM to robustly attenuate Aβ42 levels across species and modify pathogenesis in a transgenic cerebral amyloidosis mouse model.
Endothelial low-density lipoprotein receptor–related protein 1 (LRP1) protects against neurodegeneration by inhibiting the proinflammatory cyclophilin A–matrix metalloproteinase-9 pathway at the blood–brain barrier. These findings have implications for the pathophysiology and treatment of neurodegenerative disorders linked to vascular dysfunction.
Simultaneously targeting cancer-associated fibroblasts and angiogenic vessel as a treatment for TNBC
Sharma et al. present a treatment strategy by simultaneously depleting breast cancer CAFs and tumor angiogenic vessels using a rationally designed protein that induces integrin αvβ3 target-specific cell apoptosis. This offers a unique opportunity for TNBC treatment, especially for patients with dense tumor stroma.
Using single-cell RNA sequencing and TCR sequencing, Pauken et al. detect CD8+ T cell clones shared between blood and tumor in mice or melanoma patients, characterize matching clones in blood and tumor, and identify potential biomarkers for their isolation in blood.
The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation
The Trithorax Cxxc1 molecule specifically regulates the chromatin accessibility of the genes that are downregulated during priming and reactivated in the later phase in differentiating CD4 T cells. The authors show Cxxc1 deletion induces CD4 T cell hyperactivation and enhanced allergic airway inflammation.
The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection
The thymoproteasome expressed in thymic cortical epithelium optimizes the generation of CD8+ T cells. This study reveals that the thymoproteasome hardwires the TCR repertoire of CD8+ T cells with cortical positive selection independent of thymic negative selection processes.
Systematic memory B cell archiving and random display shape the human splenic marginal zone throughout life
Kibler et al. show that circulating memory B cells are systematically and comprehensively archived in the human spleen throughout life. The random, dynamic priming of archive members determines the composition of human splenic marginal zone B cells.
Cyclin D3 drives a unique form of “inertial” cell cycling responsible for clonal expansion of B cells in the germinal center dark zone.
Plasmodium falciparum–specific IgM B cells dominate in children, expand with malaria, and produce functional IgM
The role of IgM in human malaria is unclear. In a cohort study in Mali, Hopp et al. find that malaria-specific memory B cells are disproportionally IgM in children, are activated during acute malaria, and produce IgM that inhibits malaria parasite growth.
Thouvenel et al. isolate BCR sequences from Plasmodium-specific IgM+ human memory B cells, expressing them as both IgM and IgG molecules. Multimerization confers superior antigen binding and parasite restriction, highlighting an important role for memory B cell–derived IgM in immunity.
Yolk sac, but not hematopoietic stem cell–derived progenitors, sustain erythropoiesis throughout murine embryonic life
Yolk sac erythropoiesis is not replaced by hematopoietic stem cell–derived progeny up until birth. Yolk sac–derived erythroid progenitors require 10-fold lower concentrations of erythropoietin for differentiation, which confers a competitive advantage over progenitors of hematopoietic stem cell origin.
Correction: Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion