scholarly journals Rotavirus Differentially Infects and Polyclonally Stimulates Human B Cells Depending on Their Differentiation State and Tissue of Origin

2010 ◽  
Vol 84 (9) ◽  
pp. 4543-4555 ◽  
Author(s):  
Carlos F. Narváez ◽  
Manuel A. Franco ◽  
Juana Angel ◽  
John M. Morton ◽  
Harry B. Greenberg
Keyword(s):  
Cell Death ◽  
B Cells ◽  
Viral Replication ◽  
Mononuclear Cells ◽  
Cell Receptor ◽  
Human B Cells ◽  
Tissue Of Origin ◽  
Differentiation Stage

ABSTRACT We have shown previously that rotavirus (RV) can infect murine intestinal B220+ cells in vivo (M. Fenaux, M. A. Cuadras, N. Feng, M. Jaimes, and H. B. Greenberg, J. Virol. 80:5219-5232, 2006) and human blood B cells in vitro (M. C. Mesa, L. S. Rodriguez, M. A. Franco, and J. Angel, Virology 366:174-184, 2007). However, the effect of RV on B cells, especially those present in the human intestine, the primary site of RV infection, is unknown. Here, we compared the effects of the in vitro RV infection of human circulating (CBC) and intestinal B cells (IBC). RV infected four times more IBC than CBC, and in both types of B cells the viral replication was highly restricted to the memory subset. RV induced cell death in 30 and 3% of infected CBC and IBC, respectively. Moreover, RV induced activation and differentiation into antibody-secreting cells (ASC) of CBC but not IBC when the B cells were present with other mononuclear cells. However, RV did not induce these effects in purified CBC or IBC, suggesting the participation of other cells in activating and differentiating CBC. RV infection was associated with enhanced interleukin-6 (IL-6) production by CBC independent of viral replication. The infection of the anti-B-cell receptor, lipopolysaccharide, or CpG-stimulated CBC reduced the secretion of IL-6 and IL-8 and decreased the number of ASC. These inhibitory effects were associated with an increase in viral replication and cell death and were observed in polyclonally stimulated CBC but not in IBC. Thus, RV differentially interacts with primary human B cells depending on their tissue of origin and differentiation stage, and it affects their capacity to modulate the local and systemic immune responses.

scholarly journals Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

2012 ◽  
Vol 209 (6) ◽  
pp. 1201-1217 ◽  
Author(s):  
Tadashi Yokosuka ◽  
Masako Takamatsu ◽  
Wakana Kobayashi-Imanishi ◽  
Akiko Hashimoto-Tane ◽  
Miyuki Azuma ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tyrosine Phosphatase ◽  
Cell Receptor ◽  
Programmed Cell Death 1

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

scholarly journals B lymphocyte binding to E- and P-selectins is mediated through the de novo expression of carbohydrates on in vitro and in vivo activated human B cells.

1994 ◽  
Vol 94 (4) ◽  
pp. 1585-1596 ◽  
Author(s):  
A A Postigo ◽  
M Marazuela ◽  
F Sánchez-Madrid ◽  
M O de Landázuri
Keyword(s):  
B Cells ◽  
B Lymphocyte ◽  
De Novo ◽  
Human B Cells

scholarly journals Hematopoietic lineage-converted T cells carrying tumor-associated antigen-recognizing TCRs effectively kill tumor cells

2020 ◽  
Vol 8 (2) ◽  
pp. e000498
Author(s):  
Fangxiao Hu ◽  
Dehao Huang ◽  
Yuxuan Luo ◽  
Peiqing Zhou ◽  
Cui Lv ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Tumor Cells ◽  
Cell Receptor ◽  
Histocompatibility Complex ◽  
Tumor Associated Antigen ◽  
Engineered T Cells ◽  
Antitumor Immunotherapy

Tumor-associated antigen (TAA) T-cell receptor (TCR) gene-engineered T cells exhibit great potential in antitumor immunotherapy. Considering the high costs and low availability of patient-derived peripheral blood T cells, substantial efforts have been made to explore alternatives to natural T cells. We previously reported that enforced expression of Hoxb5 converted B cells into induced T (iT) cells in vivo. Here, we successfully regenerated naive OT1 (major histocompatibility complex I restricted ovalbumin antigen) iT cells (OT1-iT) in vivo by expressing Hoxb5 in pro-pre-B cells in the OT1 transgenic mouse. The OT1-iT cells can be activated and expanded in vitro in the presence of tumor cells. Particularly, these regenerated OT1-iT cells effectively eradicated tumor cells expressing the TAA (ovalbumin) both in vitro and in vivo. This study provides insights into the translational applications of blood lineage-transdifferentiated T cells in immunotherapy.

scholarly journals Epstein-Barr Virus LMP2A Alters In Vivo and In Vitro Models of B-Cell Anergy, but Not Deletion, in Response to Autoantigen

2005 ◽  
Vol 79 (12) ◽  
pp. 7355-7362 ◽  
Author(s):  
Michelle A. Swanson-Mungerson ◽  
Robert G. Caldwell ◽  
Rebecca Bultema ◽  
Richard Longnecker
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Nuclear Translocation ◽  
Cell Receptor ◽  
Barr Virus ◽  
Low Levels ◽  
Epstein Barr

ABSTRACT A significant percentage of the population latently harbors Epstein-Barr virus (EBV) in B cells. One EBV-encoded protein, latent membrane protein 2A (LMP2A), is expressed in tissue culture models of EBV latent infection, in human infections, and in many of the EBV-associated proliferative disorders. LMP2A constitutively activates proteins involved in the B-cell receptor (BCR) signal transduction cascade and inhibits the antigen-induced activation of these proteins. In the present study, we investigated whether LMP2A alters B-cell receptor signaling in primary B cells in vivo and in vitro. LMP2A does not inhibit antigen-induced tolerance in response to strong stimuli in an in vivo tolerance model in which B cells are reactive to self-antigen. In contrast, LMP2A bypasses anergy induction in response to low levels of soluble hen egg lysozyme (HEL) both in vivo and in vitro as determined by the ability of LMP2A-expressing HEL-specific B cells to proliferate and induce NF-κB nuclear translocation after exposure to low levels of antigen. Furthermore, LMP2A induces NF-κB nuclear translocation independent of BCR cross-linking. Since NF-κB is required to bypass tolerance induction, this LMP2A-dependent NF-κB activation may complete the tolerogenic signal induced by low levels of soluble HEL. Overall, the findings suggest that LMP2A may not inhibit BCR-induced signals under all conditions as previously suggested by studies with EBV immortalized B cells.

scholarly journals The Potential of IgG to Induce Murine and Human Thymic Maturation of IL-10+ B Cells (B10) Revealed in a Pilot Study

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2239
Author(s):  
Amanda Harumi Sabô Inoue ◽  
Aline Aparecida de Lima Lira ◽  
Marília Garcia de-Oliveira ◽  
Thamires Rodrigues de Sousa ◽  
Fábio da Ressureição Sgnotto ◽  
...  
Keyword(s):  
B Cells ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Allergen Challenge ◽  
Serum Samples ◽  
Peripheral Blood Mononuclear ◽  
Maturation Stages ◽  
B10 Cells

Regulatory B (B10) cells can control several inflammatory diseases, including allergies; however, the origin of peripheral B10 cells is not fully understood, and the involvement of primary lymphoid organs (PLOs) as a primary site of maturation is not known. Here, using a murine model of allergy inhibition mediated by maternal immunization with ovalbumin (OVA), we aimed to evaluate whether B10 cells can mature in the thymus and whether IgG can mediate this process. Female mice were immunized with OVA, and offspring thymus, bone marrow, spleen, lung, and serum samples were evaluated at different times and after passive transfer of purified IgG or thymocytes. A translational approach was implemented using human nonatopic thymus samples, nonatopic peripheral blood mononuclear cells (PBMCs), and IgG from atopic or nonatopic individuals. Based on the expression of CD1d on B cells during maturation stages, we suggest that B10 cells can also mature in the murine thymus. Murine thymic B10 cells can be induced in vitro and in vivo by IgG and be detected in the spleen and lungs in response to an allergen challenge. Like IgG from atopic individuals, human IgG from nonatopic individuals can induce B10 cells in the infant thymus and adult PBMCs. Our observations suggest that B10 cells may mature in the thymus and that this mechanism may be mediated by IgG in both humans and mice. These observations may support the future development of IgG-based immunoregulatory therapeutic strategies.

scholarly journals The Caspase 8 Inhibitor c-FLIPL Modulates T-Cell Receptor-Induced Proliferation but Not Activation-Induced Cell Death of Lymphocytes

2002 ◽  
Vol 22 (15) ◽  
pp. 5419-5433 ◽  
Author(s):  
Susanne M. A. Lens ◽  
Takao Kataoka ◽  
Karen A. Fortner ◽  
Antoine Tinel ◽  
Isabel Ferrero ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Receptor ◽  
Death Receptor ◽  
Cell Receptor ◽  
Caspase 8 ◽  
Activation Induced Cell Death

ABSTRACT The caspase 8 inhibitor c-FLIPL can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIPL in the T-cell compartment (c-FLIPL Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIPL Tg mice. In contrast, activation-induced cell death of T cells in c-FLIPL Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIPL Tg mice differed from Fas-deficient mice by showing no accumulation of B220+ CD4− CD8− T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIPL Tg mice. Thus, a major role of c-FLIPL in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.

scholarly journals Cd5 Maintains Tolerance in Anergic B Cells

2000 ◽  
Vol 191 (5) ◽  
pp. 883-890 ◽  
Author(s):  
Keli L. Hippen ◽  
Lina E. Tze ◽  
Timothy W. Behrens
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Immunoglobulin M ◽  
B Cell Tolerance ◽  
Cell Responses ◽  
B Cell Anergy ◽  
Clonal Anergy

Clonal anergy of autoreactive B cells is a key mechanism regulating tolerance. Here, we show that anergic B cells express significant surface levels of CD5, a molecule normally found on T cells and a subset of B-1 cells. Breeding of the hen egg lysozyme (HEL) transgenic model for B cell anergy onto the CD5 null background resulted in a spontaneous loss of B cell tolerance in vivo. Evidence for this included elevated levels of anti-HEL immunoglobulin M (IgM) antibodies in the serum of CD5−/− mice transgenic for both an HEL-specific B cell receptor (BCR) and soluble lysozyme. “Anergic” B cells lacking CD5 also showed enhanced proliferative responses in vitro and elevated intracellular Ca2+ levels at rest and after IgM cross-linking. These data support the hypothesis that CD5 negatively regulates Ig receptor signaling in anergic B cells and functions to inhibit autoimmune B cell responses.

Enhanced B Cell Activation in the Absence of CD81

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2578-2578
Author(s):  
Mrinmoy Sanyal ◽  
Rosemary Fernandez ◽  
Shoshana Levy
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Cell Receptor ◽  
Free Calcium ◽  
B Cell Activation ◽  
Membrane Reorganization ◽  
A Cell

Abstract CD81 is a component of the CD19/CD21 coreceptor complex in B cells. This tetraspanin molecule was previously shown to enable membrane reorganization in B cells responding to complement-bound antigens. Here we stimulated B cells via their B cell receptor (BCR) and demonstrate that Cd81−/− B cells fluxed higher intracellular free calcium ion along with increased phosphorylation of PLCγ2 and Syk. The stimulated Cd81−/− B cells also proliferated faster and secreted higher amounts of antibodies. Moreover, activation of the TLR4 pathway in Cd81−/− B cells induced increased proliferation and antibody secretion. Furthermore, Cd81−/− mice mounted a significantly higher immune response to T-cell independent antigens than their wildtype counterparts. Finally, analysis of Cd81−/− B cells that were generated by bone marrow transplantation into Rag1−/− mice confirmed a cell intrinsic hyperactive phenotype. Taken together, these results indicate that CD81 plays a negative role in B cell activation in vitro and in vivo.

scholarly journals Oncogene expression in autoimmune and normal peripheral blood mononuclear cells.

1986 ◽  
Vol 163 (5) ◽  
pp. 1292-1307 ◽  
Author(s):  
D M Klinman ◽  
J F Mushinski ◽  
M Honda ◽  
Y Ishigatsubo ◽  
J D Mountz ◽  
...  
Keyword(s):  
B Cells ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Isolated Cells ◽  
Peripheral Blood Mononuclear ◽  
Normal Peripheral Blood ◽  
Additional Cell ◽  
Normal Controls

PBMC from patients with autoimmune diseases and from normal controls were studied for the expression of several cellular oncogenes. Gene expression was assessed by Northern blot analysis of poly(A)+ RNA obtained from leukapheresis samples. Patients with SLE expressed significantly more c-myc protooncogene RNA than did normal controls. Increased expression of the N-ras protooncogene was found in that subset of patients whose autoimmune disease was very active. Cells from individuals with SLE, but not from those with other autoimmune illnesses, showed significantly decreased levels of the c-myb and c-fos protooncogenes. To examine the implications of these findings, B and T cells were purified from apheresis samples donated by normal volunteers. When mitogen was used to activate the B cells in vitro, their pattern of protooncogene expression changed to resemble that found in freshly isolated cells from lupus patients. These results suggest that the differences detected in the expression of protooncogenes by patients with SLE may be due to the abnormal activation of their B cells in vivo. The pattern of protooncogene expression found in patients with other autoimmune illnesses is consistent with the activation of additional cell types in those diseases.

BAFF Promotes Heightened BCR Responsiveness and Manifestations of Chronic GVHD after Allogeneic Stem Cell Transplantation

Blood ◽  
2021 ◽  
Author(s):  
Wei Jia ◽  
Jonathan C. Poe ◽  
Hsuan Su ◽  
Sarah Anand ◽  
Glenn K. Matsushima ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Cell Number ◽  
Allogeneic Bone ◽  
Donor Cells

Chronic graft versus host disease (cGVHD) patients have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major MHC-mismatched model with cGVHD-like manifestations we first examined B-lymphopenic mMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B cell number. Mice that later developed cGVHD, had significantly increased numbers of recipient fibroblastic reticular cells (FRCs) with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD since BAFF transcript in CD4+ T cells from diseased mice and patients was increased. Chronic GVHD manifestations in mice associated with high BAFF/B cell ratios and persistence of B Cell Receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR-responsiveness to surrogate antigen and NOTCH ligand. BAFF-Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR-activation or when alloantigen was present in vivo. Using T-cell depleted (BM only) BAFF-Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells and alloantibody production. We demonstrate that pathological production of BAFF promotes an altered B-cell compartment and augments BCR-responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in cGVHD patients.

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