B-lymphocyte stimulator (BLyS), a relatively recently recognized member of the tumor necrosis factor ligand family (TNF), is a potent cell-survival factor expressed in many hematopoietic cells. BLyS binds to 3 TNF-R receptors, TACI, BCMA, BAFF-R, to regulate B-cell survival, differentiation, and proliferation. The mechanisms involved in BLYS gene expression and regulation are still incompletely understood. In this study, we examined BLYS gene expression, function, and regulation in B-cell non-Hodgkin lymphoma (NHL-B) cells. Our studies indicate that BLyS is constitutively expressed in aggressive NHL-B cells, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL), playing an important role in the survival and proliferation of malignant B cells. We found that 2 important transcription factors, NF-kappaB and NFAT, are involved in regulating BLyS expression through at least one NF-kappaB and 2 NFAT binding sites in the BLYS promoter. We also provide evidence suggesting that the constitutive activation of NF-kappaB and BLyS in NHL-B cells forms a positive feedback loop associated with lymphoma cell survival and proliferation. Our findings indicate that constitutive NF-kappaB and NFAT activations are crucial transcriptional regulators of the BLyS survival pathway in malignant B cells that could be therapeutic targets in aggressive NHL-B.
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http://dx.doi.org/10.1182/blood-2005-10-4042 | DOI Listing |
Nat Commun
November 2024
Department of Chemistry, University of Georgia, Athens, GA, USA.
Calcium signaling plays a crucial role in the activation of T lymphocytes. However, modulating calcium levels to control T cell activation in vivo remains a challenge. In this study, we investigate T cell activation using 12-myristate 13-acetate (PMA)-encapsulated CaCO nanoparticles.
View Article and Find Full Text PDFJ Exp Med
January 2025
Molecular and Cellular Immunology, Great Ormond Street Institute of Child Health, University College London, London, UK.
The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease.
View Article and Find Full Text PDFFront Immunol
November 2024
Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Background: is a negative regulator of T cell activation and one of the key activators of type I interferon (IFN) and NFκB signaling via non-classical pathways. The upstream single nucleotide polymorphism of (rs2297550-G) is a genome-wide association study risk variant of systemic lupus erythematosus, and is associated with decreased expression in T cells by expression quantitative trait locus analysis.
Case Presentation: A 48-year-old female had a remittent fever, arthritis, and oral ulcers for 20 years.
Mol Ther Oncol
December 2024
Antibody Engineering Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The E6 and E7 oncoproteins of human papillomavirus (HPV) are considered promising targets for HPV-related cancers. In this study, we evaluated novel T cell receptor mimic (TCRm) nanobodies targeting the E6 peptide complexed with human leukocyte antigen (HLA)-A∗02:01 in the chimeric antigen receptor (CAR) format. We isolated two dromedary camel nanobodies, F5 and G9, through phage display screening.
View Article and Find Full Text PDFCell Rep Med
November 2024
Oncology R&D, AstraZeneca, Waltham, MA, USA. Electronic address:
In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors.
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