Varga et al. identified Notch3 as a promoter of tumor progression and metastasis in a mouse model of advanced colorectal cancer. In CRC patients, NOTCH3 expression was associated with poor overall survival. These findings feature NOTCH3 as putative therapeutic target for advanced CMS4 CRC patients.
Beyond genes and transcription factors: A potential mechanism for the pathogenesis of cerebral cavernous malformations
In this commentary on Hong et al., Bill Muller explains the significance of their findings as a mechanism for the non–cell autonomous pathogenesis of CCMs and the potential relevance of targeting ADAMTS5 therapeutically in this condition, for which the only current option is surgery.
An extensive crosstalk between host and intestinal microbiota contributes to the development and maturation of intestinal epithelium and immune system. This review details the interplay between nucleotide-binding domain leucine-rich repeat containing proteins (NLR, or NOD-like receptors) signaling to host-microbiota homeostasis.
COVID-19 may result from a hyperactive but asynchronized immune system causing a cacophony of severe tissue damage without optimal viral clearance and immunological resolution. A general strategy for COVID-19 treatment is to correct the immune dysregulation at the late stage of disease.
Brief Definitive Report
Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
Activated AKT is a tumorigenic driver in ganglioneuroma, and inhibition of the downstream AKT target mTOR may serve as a means to shrink large ganglioneuromas prior to resection in order to reduce surgical morbidity.
This study shows that IgG memory B cells developing in HBV vaccinees and in rare individuals able to naturally control chronic HBV infection express a panoply of neutralizing antibodies, some of which are potent viremia suppressors in vivo.
We explored the nature of the human CD4 T cell immunodominance to influenza H1 hemagglutinin and demonstrate that the naïve repertoire is very broad, while the memory repertoire becomes selected toward peptides with a high likelihood to be processed and presented by dendritic cells.
A committed tissue-resident memory T cell precursor within the circulating CD8+ effector T cell pool
Following local inflammation, CD8+ T cells develop into tissue-resident memory T cells (TRM). Through combined lineage tracing and single-cell transcriptome analysis, the authors show that the circulating T cell pool harbors TRM precursors that commit to the TRM fate before tissue entry.
Liver X receptors (LXRs) orchestrate cholesterol metabolism with diverse metabolic and immune functions. Chan et al. show that in the thymus, thymic epithelial cells protect against involution and promote regeneration, whereas T cells require LXRs to escape negative selection.
Th17 cells undergo metabolic reprogramming towards glycolysis to support their differentiation and pathogenicity. Damasceno et al. report that PKM2, a glycolytic enzyme, plays a nonmetabolic role in mediating Th17 cell differentiation and autoimmune neuroinflammation by fine-tuning STAT3 activation.
STAT3 transcription factor activity is critical for Th17 cell development. Poholek et al. report that STAT3 maintains proliferation and function of autoimmune effector Th17 cells by limiting STAT1 activation and sustaining mitochondrial membrane potential to allow cytokine production in response to TCR stimulation.
PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification
Delgado-Benito et al. identify the protein Pdap1 as a regulator of mature B cell homeostasis. Pdap1 protects mature B cells against chronic induction of the integrated stress response and promotes both their survival and antibody gene diversification by CSR and SHM.
CCMs arise due to increased MEKK3-KLF2/4 signaling in brain endothelial cells, but the downstream mechanisms of CCM formation remain unclear. Hong et al. show that expression of the ADAMTS5 protease and proteolytic cleavage of the matrix proteoglycan versican by CCM-deficient endothelial cells contribute to CCM formation.
Patients with severe developmental delay, dysmorphism, and brain abnormalities were identified as having pathogenic mutations in EXOC2, a critical component of the exocyst complex involved in vesicle trafficking, which caused secretory vesicle transport defects in patient-derived cell lines.
Single-cell transcriptomic analysis of germinal center B cells identifies multiple linked populations, most of which represent cell of origin of lymphomas. The newly identified cell of origin of diffuse large B cell lymphoma informs on novel prognostic subgroups.
AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer
Varga et al. describe a novel genetically modified mouse model of human, poor-prognosis mesenchymal colorectal cancer. Using this model, they identify NOTCH3 as a potential therapeutic target for this specific colorectal cancer subtype.
C-C chemokine receptor type 2 (CCR2) expressed on monocytes facilitates their recruitment to tumors. Here, Fein et al. show that CCR2 signaling in cancer cells suppresses immune control of tumors, in part by reducing CD103+ dendritic cell recruitment.
Profiling HPV-16–specific T cell responses reveals broad antigen reactivities in oropharyngeal cancer patients
Proteome-wide profiling of HPV-specific T cell immunity in oropharyngeal cancer (OPC) patients reveals broad and multiple antigen-specific reactivities directed to HPV-encoded proteins E1, E2, E4, E5 E6, E7, and L1. These observations provide novel insights for future development of cellular immunotherapies for HPV-associated OPC patients.
LCN2 is an osteoblast-enriched secreted protein that regulates food intake. Here, the authors show that LCN2 is upregulated during obesity and diabetes as a protective mechanism to counteract obesity-induced glucose intolerance by decreasing food intake and promoting adaptive β-cell proliferation.
Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis
The authors show that SpA synovitis comprises less sTNF and more tmTNF expression compared to RA synovitis associated with less active ADAM17. Moreover, tmTNF overexpression induces SpA-like pathophysiology in mice. tmTNF signaling through TNF-RI induced inflammation, but not osteoproliferation.
FcRn and CD32a form a ternary complex under acidic conditions and act together in determining responses to IgG immune complexes. The human autoimmune disease–associated CD32a-H131 variant more avidly forms this ternary complex, leading to greater FcRn-dependent immune responses to IgG.