scholarly journals Marek's Disease Viral Interleukin-8 Promotes Lymphoma Formation through Targeted Recruitment of B Cells and CD4+CD25+T Cells

2012 ◽  
Vol 86 (16) ◽  
pp. 8536-8545 ◽  
Author(s):  
Annemarie T. Engel ◽  
Ramesh K. Selvaraj ◽  
Jeremy P. Kamil ◽  
Nikolaus Osterrieder ◽  
Benedikt B. Kaufer
Keyword(s):  
T Cells ◽  
B Cells ◽  
Splice Variants ◽  
Tumor Development ◽  
Marek's Disease ◽  
Interleukin 8 ◽  
Start Codon ◽  
Marek’S Disease ◽  
Viral Oncoprotein

Marek's disease virus (MDV) is a cell-associated and highly oncogenic alphaherpesvirus that infects chickens. During lytic and latent MDV infection, a CXC chemokine termed viral interleukin-8 (vIL-8) is expressed. Deletion of the entire vIL-8 open reading frame (ORF) was shown to severely impair disease progression and tumor development; however, it was unclear whether this phenotype was due to loss of secreted vIL-8 or of splice variants that fuse exons II and III of vIL-8 to certain upstream open reading frames, including the viral oncoprotein Meq. To specifically examine the role of secreted vIL-8 in MDV pathogenesis, we constructed a recombinant virus, vΔMetvIL-8, in which we deleted the native start codon from the signal peptide encoding exon I. This mutant lacked secreted vIL-8 but did not affect Meq–vIL-8 splice variants. Loss of secreted vIL-8 resulted in highly reduced disease and tumor incidence in animals infected with vΔMetvIL-8 by the intra-abdominal route. Although vΔMetvIL-8 was still able to spread to naïve animals by the natural route, infection and lymphomagenesis in contact animals were severely impaired.In vitroassays showed that purified recombinant vIL-8 efficiently binds to and induces chemotaxis of B cells, which are the main target for lytic MDV replication, and also interacts with CD4+CD25+T cells, known targets of MDV transformation. Our data provide evidence that vIL-8 attracts B and CD4+CD25+T cells to recruit targets for both lytic and latent infection.

scholarly journals The Transcriptional Landscape of Marek’s Disease Virus in Primary Chicken B Cells Reveals Novel Splice Variants and Genes

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 264 ◽  
Author(s):  
Luca Bertzbach ◽  
Florian Pfaff ◽  
Viktoria Pauker ◽  
Ahmed Kheimar ◽  
Dirk Höper ◽  
...  
Keyword(s):  
B Cells ◽  
Disease Virus ◽  
Splice Variants ◽  
Transcriptome Assembly ◽  
Marek's Disease Virus ◽  
Marek's Disease ◽  
Target Cells ◽  
Marek’S Disease Virus ◽  
Marek’S Disease ◽  
Transcriptional Landscape

Marek’s disease virus (MDV) is an oncogenic alphaherpesvirus that infects chickens and poses a serious threat to poultry health. In infected animals, MDV efficiently replicates in B cells in various lymphoid organs. Despite many years of research, the viral transcriptome in primary target cells of MDV remained unknown. In this study, we uncovered the transcriptional landscape of the very virulent RB1B strain and the attenuated CVI988/Rispens vaccine strain in primary chicken B cells using high-throughput RNA-sequencing. Our data confirmed the expression of known genes, but also identified a novel spliced MDV gene in the unique short region of the genome. Furthermore, de novo transcriptome assembly revealed extensive splicing of viral genes resulting in coding and non-coding RNA transcripts. A novel splicing isoform of MDV UL15 could also be confirmed by mass spectrometry and RT-PCR. In addition, we could demonstrate that the associated transcriptional motifs are highly conserved and closely resembled those of the host transcriptional machinery. Taken together, our data allow a comprehensive re-annotation of the MDV genome with novel genes and splice variants that could be targeted in further research on MDV replication and tumorigenesis.

scholarly journals THU0035 OX40L EXPRESSING NEUTROPHILS INDUCE CD4 T FOLLICULAR AND PERIPHERAL HELPER CELL DIFFERENTIATION IN SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 230.2-231
Author(s):  
A. Pappalardo ◽  
E. Wojciechowski ◽  
I. Odriozola ◽  
I. Douchet ◽  
N. Merillon ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Cd4 T Cells ◽  
Close Contact ◽  
Memory B Cells ◽  
Systemic Lupus ◽  
Research Support

Background:Neutrophils have been described as potent antigen-presenting cells able to activate T cells by MHC/TCR interaction and costimulatory molecules in tumor immunity. However, little is known about the direct interaction between neutrophils and CD4 T cells with respect to systemic lupus erythematosus (SLE). We have previously shown that OX40L expressed by monocytes from SLE patients promote the differentiation of naïve and memory cells into IL21 secreting T cells that are able to help B cells1,2.Objectives:In this study, we investigate OX40L expression on neutrophils from SLE patients and contribution of these OX40L+neutrophils in SLE pathogenesis to modulation of the B cell helper role of CD4 T cells.Methods:Surface expression of co-stimulatory molecules (OX40L, ICOSL, GITRL, 4-1BBL) on neutrophils from SLE patients and healthy donors (HD) was measured by flow cytometry (FC). Neutrophils from HD were stimulated with TLR7 or TLR8 agonists and IFNα after 5 hours of culture, OX40L expression was measured by FC and Western Blotting. CD4 T cells were cultured with the stimulated neutrophils for 3 days. At the end of the co-culture, percentages of IL21-expressing T follicular (Tfh) and peripheral helper (Tph) cells measured by FC. These generated T cells were also cultured in the presence of memory B cells. After 5 days of co-culture, plasmablast generation and Ig levels were assessed by FC and ELISA, respectively. Inhibition of OX40-OX40L interaction in vitro was achieved using ISB 830, a novel anti-OX40 mAb currently used in clinical trials.Results:Among the co-stimulatory molecules tested, percentages of OX40L+neutrophils in SLE (n=54) were increased compared to HD (n=25)(mean + SD: HD = 1,34%±1.62 vs SLE = 4,53%±8.1; p=0.29). OX40L expression positively correlated with SLE disease activity score (SLEDAI) (p = 0,04; r = 0,31) and with anti-DNA antibodies (p= 0,04, r = 0,33). Of note, the percentage of OX40L+neutrophils was higher in anti-sm-RNP+patients (n=16, mean= 9%±9.8), compared to anti-sm-RNP-patients (n=27, mean = 1,4%±2.5; p = 0,02). The percentage of OX40L+neutrophils was higher in patients with class III or IV lupus nephritis, and inflammatory infiltrate within the kidney biopsy disclosed OX40L+neutrophils, in close contact with T cells. Neutrophils from HD express OX40L with TLR8 agonist, or IFNα priming followed by TLR7 agonist. When memory CD4 T cells were cultured in the presence of TLR8-stimulated neutrophils, the proportion of IL21-expressing Tfh (CXCR5+PD1+) and Tph (CXCR5-PD1hi) were increased, compared to culture with unstimulated neutrophils. This process was dependent on OX40-OX40L interactions, since in vitro treatment with the anti-OX40 blocking antibody ISB 830, inhibited the differentiation of memory T cells into Tfh and Tph. Both generated Tfh and Tph were able to promote the differentiation of memory B cells into Ig-secreting plasmablasts.Conclusion:Our results disclose an unprecedented phenomenon where cross-talk between TLR7/8-activated neutrophils and CD4 lymphocytes operates through OX40L-OX40 costimulation, and neutrophils promote the differentiation of pro-inflammatory Tfh and Tph, as well as IL21 production. Therefore, OX40L/OX40 should be considered as a potentially therapeutic axis in SLE patients.References:[1]Jacquemin et al. Immunity 2015;[2]Jacquemin et al. JCI Insight 2018Disclosure of Interests:Angela Pappalardo Grant/research support from: Ichnos Sciences, Elodie Wojciechowski: None declared, Itsaso Odriozola: None declared, Isabelle Douchet: None declared, Nathalie Merillon: None declared, Andrea Boizard-Moracchini: None declared, Pierre Duffau: None declared, Estibaliz Lazaro: None declared, Marie-Agnes Doucey Employee of: Ichnos Sciences, Lamine Mbow Employee of: Ichnos Sciences, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Patrick Blanco Grant/research support from: Ichnos Sciences

scholarly journals Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Colado ◽  
Esteban Enrique Elías ◽  
Valeria Judith Sarapura Martínez ◽  
Gregorio Cordini ◽  
Pablo Morande ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Immunomodulatory Effects ◽  
Immunoglobulin Preparations

AbstractHypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

scholarly journals INDUCTION OF A HEMOLYSIN RESPONSE IN VITRO

1971 ◽  
Vol 133 (6) ◽  
pp. 1325-1333 ◽  
Author(s):  
Klaus-Ulrich Hartmann
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
Close Contact ◽  
Precursor Cells ◽  
Spleen Cells ◽  
High Concentrations ◽  
Thymus Cells ◽  
Bone Marrow Chimeras

Spleen cells of bone marrow chimeras (B cells) and of irradiated mice injected with thymus cells and heterologous erythrocytes (educated T cells) were mixed and cultured together (17). The number of PFC developing in these cultures was dependent both on the concentration of the B cells and of the educated T cells. In excess of T cells the number of developing PFC is linearly dependent on the number of B cells. At high concentrations of T cells more PFC developed; the increase in the number of PFC was greatest between the 3rd and 4th day of culture. Increased numbers of educated T cells also assisted the development of PFC directed against the erythrocytes. It is concluded that the T cells not only play a role during the triggering of the precursor cells but also during the time of proliferation of the B cells; close contact between B and T cells seems to be needed to allow the positive activity of the T cells.

CD40 LIGAND GENE DEFECTS RESPONSIBLE FOR X-LINKED HYPER-IgM SYNDROME

PEDIATRICS ◽  
1994 ◽  
Vol 94 (2) ◽  
pp. 280-280
Author(s):  
Arden Levy ◽  
Andrew Liu
Keyword(s):  
T Cells ◽  
B Cells ◽  
Bacterial Infections ◽  
Point Mutations ◽  
Cd40 Ligand ◽  
Research Groups ◽  
Immune Disorder ◽  
Hyper Igm Syndrome ◽  
Hyper Igm

Purpose of the Studies. Hyper-IgM immunodeficiency is characterized by recurrent bacterial infections, normal or elevated IgM, and markedly decreased IgG, IgA, and IgE. Previous research suggested that the T cells of these patients are defective in their ability to help B cells make functional antibody. CD40 ligand (CD4OL) is a membrane glycoprotein on activated T helper cells and binds the CD40 molecule expressed on B cells, and induces proliferation and immunoglobulin class switching (in conjunction with IL-4). The gene for the CD4OL has been mapped to position q26.3-q27.1 on chromosome X (same as the Hyper-IgM gene and the area of isotype switching). Several research groups sought to determine if the immunodeficiency in Hyper-IgM patients is due to defective CD4OL. Findings. The five papers listed above document the work of different research groups that simultaneously found abnormalities in the CD4OL gene in a total of 16 patients with X-linked Hyper-IgM syndrome. Different mutations of the CD4OL gene have been discovered, including point mutations, deletions, and nonsense sequences. Mutant version of CD4OL taken from Hyper IgM patients were unable to "help" B cells in vitro. Thus, deficient CD40/CD40L interactions between B and T cells results in severely impaired immunity. Restricted CD40L gene expression to T cells may ultimately allow gene therapy as treatment. Reviewers' Comments. A concise editorial by Jean Marx entitled "Cell Communication Failure Leads to Immune Disorder" describes this landmark research and accompanies the Spriggs article in the February 12th issue of Science (pp. 896-897). This discovery may not only lead to treatment of this disorder, but also modification of other less favorable immune responses.

CD40 LIGAND MUTATIONS IN X-LINKED IMMUNODEFICIENCY WITH HYPER-IgM

PEDIATRICS ◽  
1994 ◽  
Vol 94 (2) ◽  
pp. 280-280
Author(s):  
Arden Levy ◽  
Andrew Liu
Keyword(s):  
T Cells ◽  
B Cells ◽  
Bacterial Infections ◽  
Point Mutations ◽  
Cell Communication ◽  
Cd40 Ligand ◽  
Research Groups ◽  
Immune Disorder ◽  
Hyper Igm

Purpose of the Studies. Hyper-IgM immunodeficiency is characterized by recurrent bacterial infections, normal or elevated IgM, and markedly decreased IgG, IgA, and IgE. Previous research suggested that the T cells of these patients are defective in their ability to help B cells make functional antibody. CD40 ligand (CD4OL) is a membrane glycoprotein on activated T helper cells and binds the CD40 molecule expressed on B cells, and induces proliferation and immunoglobulin class switching (in conjunction with IL-4). The gene for the CD4OL has been mapped to position q26.3-q27.1 on chromosome X (same as the Hyper-IgM gene and the area of isotype switching). Several research groups sought to determine if the immunodeficiency in Hyper-IgM patients is due to defective CD4OL. Findings. The five papers listed above document the work of different research groups that simultaneously found abnormalities in the CD4OL gene in a total of 16 patients with X-linked Hyper-IgM syndrome. Different mutations of the CD4OL gene have been discovered, including point mutations, deletions, and nonsense sequences. Mutant version of CD4OL taken from Hyper IgM patients were unable to "help" B cells in vitro. Thus, deficient CD40/CD40L interactions between B and T cells results in severely impaired immunity. Restricted CD40L gene expression to T cells may ultimately allow gene therapy as treatment. Reviewers' Comments. A concise editorial by Jean Marx entitled "Cell Communication Failure Leads to Immune Disorder" describes this landmark research and accompanies the Spriggs article in the February 12th issue of Science (pp. 896-897). This discovery may not only lead to treatment of this disorder, but also modification of other less favorable immune responses.

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