scholarly journals RNA-Binding Protein Expression Alters Upon Differentiation of Human B Cells and T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Nordin D. Zandhuis ◽  
Benoit P. Nicolet ◽  
Monika C. Wolkers
Keyword(s):  
T Cells ◽  
B Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Lymphocytes ◽  
Lymphocyte Function ◽  
Memory Cells ◽  
Comprehensive Overview ◽  
Lymphocyte Differentiation ◽  
Human B Cells

B cells and T cells are key players in the defence against infections and malignancies. To exert their function, B cells and T cells differentiate into effector and memory cells. Tight regulation of these differentiation processes is key to prevent their malfunction, which can result in life-threatening disease. Lymphocyte differentiation relies on the appropriate timing and dosage of regulatory molecules, and post-transcriptional gene regulation (PTR) is a key player herein. PTR includes the regulation through RNA-binding proteins (RBPs), which control the fate of RNA and its translation into proteins. To date, a comprehensive overview of the RBP expression throughout lymphocyte differentiation is lacking. Using transcriptome and proteome analyses, we here catalogued the RBP expression for human B cells and T cells. We observed that even though the overall RBP expression is conserved, the relative RBP expression is distinct between B cells and T cells. Differentiation into effector and memory cells alters the RBP expression, resulting into preferential expression of different classes of RBPs. For instance, whereas naive T cells express high levels of translation-regulating RBPs, effector T cells preferentially express RBPs that modulate mRNA stability. Lastly, we found that cytotoxic CD8+ and CD4+ T cells express a common RBP repertoire. Combined, our study reveals a cell type-specific and differentiation-dependent RBP expression landscape in human lymphocytes, which will help unravel the role of RBPs in lymphocyte function.

scholarly journals Mapping RNA-binding proteins in human B cells and T cells upon differentiation

2021 ◽  
Author(s):  
Nordin D. Zandhuis ◽  
Benoit P. Nicolet ◽  
Monika C. Wolkers
Keyword(s):  
T Cells ◽  
B Cells ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Lymphocytes ◽  
Lymphocyte Function ◽  
Memory Cells ◽  
Lymphocyte Differentiation ◽  
Human B Cells

B cells and T cells are key players in the defence against infections and malignancies. To exert their function, B cells and T cells differentiate into effector and memory cells. Tight regulation of these differentiation processes is key to prevent their malfunction, which can result in life-threatening disease. Lymphocyte differentiation relies on the appropriate timing and dosage of regulatory molecules, and post-transcriptional gene regulation (PTR) is a key player herein. PTR includes the regulation through RNA-binding proteins (RBPs), which control the fate of RNA and its translation into proteins. To date, a comprehensive RBP expression map throughout lymphocyte differentiation is lacking. Using transcriptome and proteome analyses, we here provide an RBP expression map for human B cells and T cells. We observed that even though the overall RBP expression is conserved, the relative RBP expression is distinct between B cells and T cells. Differentiation into effector and memory cells alters the RBP expression, resulting into preferential expression of different classes of RBPs. For instance, whereas naive T cells express high levels of translation-regulating RBPs, effector T cells preferentially express RBPs that modulate mRNA stability. Lastly, we found that cytotoxic CD8+ and CD4+ T cells express a common RBP repertoire. Combined, our study reveals a cell type-specific and differentiation-dependent RBP expression landscape in human lymphocytes, which will help unravel the role of RBPs in lymphocyte function.

scholarly journals Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

2020 ◽  
Vol 11 ◽  
Author(s):  
Jean-Marie Berthelot ◽  
Frédéric Lioté ◽  
Yves Maugars ◽  
Jean Sibilia
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
Human Lymphocytes ◽  
Dna Damages ◽  
Human B Cells ◽  
Antigen Presenting ◽  
Microbial Dna ◽  
Th2 Differentiation

Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.

A Potential Therapeutic Target RNA-binding Protein, Arid5a for the Treatment of Inflammatory Disease Associated with Aberrant Cytokine Expression

2018 ◽  
Vol 24 (16) ◽  
pp. 1766-1771 ◽  
Author(s):  
Kazuya Masuda ◽  
Tadamitsu Kishimoto
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Severe Sepsis ◽  
Inflammatory Cytokines ◽  
Binding Proteins ◽  
Rna Binding ◽  
Cytokine Production ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Transcriptional Level

Background: Infection, tissue damage and aging can cause inflammation with high levels of inflammatory cytokines. Overproduction of inflammatory cytokines often leads to systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock. However, prominent therapeutic targets have not been found, although the incidence of sepsis is likely to increase annually. Our recent studies indicate that some RNA-binding proteins, which control gene expression of inflammatory cytokines at the post-transcriptional level, may play a critical role in inflammatory diseases such as sepsis. Results: 1) One of the RNA-binding proteins, AT-rich interactive domain-containing 5a (Arid5a) promotes cytokine production through control of mRNA half-lives of pro-inflammatory molecules such as IL-6, STAT3, T-bet, and OX40 in activated macrophages and T cells. Arid5a KO mice are refractory to endotoxin shock, bleomycininduced lung injury, and inflammatory autoimmune disease. 2) Chlorpromazine (CPZ), which is recognized as a psychotic drug, impairs post-transcriptional gene expression of Il6 in LPS-stimulated macrophages: CPZ inhibits the binding activity of Arid5a to the 3’UTR of Il6 mRNA, thereby destabilizing Il6 mRNA possibly through suppression of Arid5a expression. 3) CPZ has strong suppressive effects on cytokine production such as TNF-α in vivo. Mice with treatment of CPZ are resistant to lipopolysaccharide (LPS)-induced shock. Conclusion: Thus, Arid5a contributes to the activation of macrophages and T cells through positive control of mRNA half-lives of inflammatory cytokines and its related molecules, which might lead to cytokine storm. Interestingly, Arid5a was identified from an inhibitory effect of CPZ on IL-6 production in macrophages activated by LPS. Therefore, CPZ derivatives or Arid5a inhibitors may have a potential to suppress severe sepsis through control of post-transcriptional gene expression.

scholarly journals Defining the RBPome of primary T helper cells to elucidate higher-order Roquin-mediated mRNA regulation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kai P. Hoefig ◽  
Alexander Reim ◽  
Christian Gallus ◽  
Elaine H. Wong ◽  
Gesine Behrens ◽  
...  
Keyword(s):  
T Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
T Helper ◽  
Signal Transducers ◽  
Mrna Regulation ◽  
Costimulatory Receptor ◽  
Mrna Targets ◽  
Human T Cell ◽  
Transcriptional Gene Regulation

AbstractPost-transcriptional gene regulation in T cells is dynamic and complex as targeted transcripts respond to various factors. This is evident for the Icos mRNA encoding an essential costimulatory receptor that is regulated by several RNA-binding proteins (RBP), including Roquin-1 and Roquin-2. Here, we identify a core RBPome of 798 mouse and 801 human T cell proteins by utilizing global RNA interactome capture (RNA-IC) and orthogonal organic phase separation (OOPS). The RBPome includes Stat1, Stat4 and Vav1 proteins suggesting unexpected functions for these transcription factors and signal transducers. Based on proximity to Roquin-1, we select ~50 RBPs for testing coregulation of Roquin-1/2 targets by induced expression in wild-type or Roquin-1/2-deficient T cells. Besides Roquin-independent contributions from Rbms1 and Cpeb4 we also show Roquin-1/2-dependent and target-specific coregulation of Icos by Celf1 and Igf2bp3. Connecting the cellular RBPome in a post-transcriptional context, we find contributions from multiple RBPs to the prototypic regulation of mRNA targets by individual trans-acting factors.

scholarly journals Production and characterization of a bispecific IgG capable of inducing T-cell-mediated lysis of malignant B cells

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3343-3349 ◽  
Author(s):  
BK Link ◽  
GJ Weiner
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Hybridoma Cells ◽  
Activated T Cells ◽  
Human B Cells ◽  
B Cell Malignancy ◽  
Cell Malignancy

Abstract Bispecific monoclonal antibodies (bsabs) recognizing both CD3 and a tumor antigen can redirect T-cell-mediated cytotoxicity toward cells bearing that antigen. Such bsabs have been shown to be more effective than monospecific monoclonal antibodies (MoAbs) at preventing tumor growth in animal models of B-cell malignancy. The current studies describe the production and preliminary evaluation of a bsab designed to induce the lysis of malignant human B cells by human T cells. The bsab was obtained from a hybrid-hybridoma cell line produced by fusing OKT3-secreting hybridoma cells with hybridoma cells that secrete 1D10. 1D10 is an MoAb that recognizes an antigen found on a majority of malignant human B cells that has not been detected to a significant degree on normal resting or activated lymphocytes. High performance liquid chromatography (HPLC) was used to separate bsab from monospecific antibodies that were also present in the hybrid-hybridoma antibody product. The bsab was then evaluated in vitro for its ability to induce lysis of malignant B cells by activated T cells. The bsab consistently induced extensive lysis in vitro of 1D10 (+) cells, including both cell lines and cells obtained from patients with a variety of B-cell malignancies. No such effect was seen with activated T cells alone or activated T cells with monospecific antibody. No increased lysis was seen with 1D10 (-) cell lines. The bsab also mediated lysis of malignant B cells by autologous T cells. We conclude bsab containing an OKT3 arm and a 1D10 arm can induce T-cell-mediated lysis in a manner that is both potent and specific. This supports further evaluation of this bsab as a potential immunotherapy of B-cell malignancy.

scholarly journals Expression of the G-protein--coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 830-840 ◽  
Author(s):  
R Forster ◽  
T Emrich ◽  
E Kremmer ◽  
M Lipp
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cord Blood ◽  
G Protein ◽  
Blood Cells ◽  
Memory Cells ◽  
T Helper ◽  
G Protein Coupled Receptor ◽  
Color Flow ◽  
G Protein Coupled

Abstract The G-protein-coupled receptor BLR1 related to receptors for chemokines and neuropeptides has been identified as the first lymphocyte-specific member of the gene family characterized by seven transmembrane-spanning regions. Using a high-affinity anti-BLR1 monoclonal antibody (MoAb) and three-color flow cytometry it is shown that BLR1 expression on peripheral blood cells is limited to B cells and to a subset of CD4+ (14%) and CD8+ (2%) lymphocytes. T cells expressing BLR1 were positive for CD45R0, were negative for interleukin-2 receptors, show high levels of CD44, and show low levels of L-selectin. The majority of CD4+ cells originating from secondary lymphatic tissue, but none of cord blood- derived T cells, express BLR1. These observations suggest that BLR1 is a marker for memory T cells. Furthermore, BLR1 expression was detected on all CD19+ peripheral or tonsillar B lymphocytes, but only on a fraction of cord blood cells and bone marrow cells expressing CD19, sIgM, or sIgD. Interestingly, activation of both mature B and T cells by CD40 MoAb and CD3 MoAb, respectively, led to complete downregulation of BLR1. These data suggest that the G-protein-coupled receptor BLR1 is involved in functional control of mature recirculating B cells and T- helper memory cells participating in cell migration and cell activation.

scholarly journals Maturation of Lymphocyte Immunophenotypes and Memory T Helper Cell Differentiation During Development in Mice

2000 ◽  
Vol 8 (1) ◽  
pp. 47-60 ◽  
Author(s):  
Omar R. Fagoaga ◽  
Steven. M. Yellon ◽  
Sandra. L. Nehlsen-Cannarella
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
Cell Subset ◽  
T Helper Cell ◽  
Natural Killers ◽  
Memory Cells ◽  
Spleen Lymphocyte ◽  
T Helper

The goal of this study was to systematically investigate the ontogeny of lymphoid populations throughout postnatal development. In CD-1 mice, peak lymphocyte numbers occurred in blood on postnatal day 10 (dl0) including those for natural killers (NK1.1), B cells (CD19), T helper (CD3CD4), naïve T helper (CD4CD62LposCD44low), memory T helper (CD4CD62LnegCD44high), and T cytotoxic (CD3CD8) cells. As percent of total lymphocytes, peaks were achieved by d10 for all T helper subtypes but not B cells which declined to a nadir. In spleen, lymphocyte numbers increased exponentially after d10. Proportionately, NK and T cells peaked on d10, declined by d20, and increased 2–3-fold by d45. Naive T cells constituted the majority of lymphocytes during development while memory cells gained to 2.2% (blood) and 12 % (spleen) by d20. C57BL/6 mice had similar profiles except that the B cell nadir and T cell subset peaks were at d5. Peripheralization of critical numbers of lymphocytes by d10, and importantly, development of a repertoire of memory cells by d20, may define immune response capabilities that close the period of immaturity for the neonate.

ZAP-70 Expression in Human B cells: Analysis of Normal Cells and Acute Lymphoblastic Leukemia (ALL) Cells with Pro/Pre B Phenotype.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4443-4443
Author(s):  
Marta Crespo ◽  
Neus Villamor ◽  
Eva Gine ◽  
Dolors Colomer ◽  
Teresa Marafioti ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Protein Tyrosine Kinase ◽  
Lymphoblastic Leukemia ◽  
Human Lymphocytes ◽  
Critical Role ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Qrt Pcr ◽  
Human B Cells

Abstract ZAP-70 is a protein tyrosine kinase of the Syk/ZAP-70 family that plays a critical role in the signal transduction from the T-cell receptor. In human lymphocytes, ZAP-70 gene has been reported to be expressed in T and NK derived cells, and in IgVH unmutated B-chronic lymphocytic leukemia cells. More recently, ZAP-70 expression has been shown to be required for the development of pro-B cells to pre-B cells in mice. To ascertain the expression of ZAP-70 gene in human immature B-cell stages, we analyzed ZAP-70 protein and/or mRNA in normal human B cells at different stages of B cell maturation, including pro/pre-B cells and tumoral cells from 20 B-ALL. ZAP-70 expression was assessed by flow cytometry (FC), immunofluorescence (IF), and/or by quantitative real time RT-PCR (QRT-PCR). In normal bone marrow, ZAP-70 expression was found only in T and in immature B cells (CD19+/CD10+/CD20 −). Moreover, T cells -but no mature B cells- from normal tonsil expressed ZAP-70, as assessed by QRT-PCR and IF. In B-ALLs, a high ZAP-70 expression by FC was observed in 9/13 cases (mean, 82.6%, range 60–99%), whereas in 4 cases ZAP-70 was barely detectable (mean, 13%). By QRT-PCR, 10/16 B-ALLs showed levels of expression similar to ZAP-70 non-expressing cell lines and normal B-cells, whereas in the remaining cases ZAP-70 expression was 3–4 times higher than in normal mature B-cells. Taken together, a high expression of ZAP-70 was found in 11/21 (52%) B-ALLs. No relationship was observed between the level of ZAP-70 expression and the B-ALL maturation status. In conclusion, among normal B cell subsets ZAP-70 expression is restricted to B-cells with pro/pre phenotype. In addition, ZAP-70 is expressed in 52% of B-ALLs, probably as a reflection of their B-cell origin.

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