scholarly journals T-independent and T-dependent B lymphoblasts: helper T cells prime for interleukin 2-induced growth and secretion of immunoglobulins that utilize downstream heavy chains.

1991 ◽  
Vol 173 (3) ◽  
pp. 687-697 ◽  
Author(s):  
M S Forman ◽  
E Puré
Keyword(s):  
B Cells ◽  
Interleukin 2 ◽  
Surface Adhesion ◽  
Th Cells ◽  
Heavy Chains ◽  
Enhanced Expression ◽  
Different Populations ◽  
And Function

Resting B cells enlarge, enter the cell cycle, and change their surface phenotype when activated via the surface immunoglobulin (Ig) receptor, but subsequent cell growth and antibody production is relatively limited. To identify stimuli that might prime B cells for enhanced function in vitro, we have compared the effects of anti-Ig with helper T (Th) cells on the formation of B lymphoblasts and the subsequent ability of the blasts to grow and secrete Ig. The B blasts first were induced by either anti-Ig, anti-Ig plus T cell-derived lymphokines, or alloreactive T blasts. Each population of B blasts showed enhanced expression of cell surface adhesion molecules, interleukin 2 receptor (IL-2R) p55, and MHC products, as well as decreased expression of IgD. The allo-activated B blasts were distinctive in expressing low levels of Thy-1 and increased reactivity with peanut agglutinin, a marker of germinal center B blasts in situ. The function of the different populations of B blasts was also different. Whereas anti-Ig or anti-Ig plus lymphokines primed for enhanced responses to lipopolysaccharide (LPS), the B blasts induced by Th cells were insensitive to LPS. B lymphoblasts that had been activated in the presence of helper factors or Th cells responded vigorously to recombinant IL-2 with growth and Ig secretion, and this response was enhanced in the presence of anti-Ig. The B blasts activated directly by Th cells, but not by anti-Ig plus lymphokines, were primed to secrete high levels of IgG1 and IgA. Therefore, the phenotype and function of a B lymphoblast depends upon the manner in which it is primed. When primed by Th cells, IL-2 proves to be the predominant mediator of clonal expansion and antibody secretion.

scholarly journals Altered folate binding protein expression and folate delivery are associated with congenital hydrocephalus in the hydrocephalic Texas rat

2018 ◽  
Vol 39 (10) ◽  
pp. 2061-2073 ◽  
Author(s):  
Alicia Requena Jimenez ◽  
Naila Naz ◽  
Jaleel A Miyan
Keyword(s):  
Folate Receptor ◽  
Cortical Cell ◽  
Regulatory Function ◽  
Folate Binding Protein ◽  
In Vitro Proliferation ◽  
Cycle Arrest ◽  
Csf Levels ◽  
And Function

Hydrocephalus (HC) is an imbalance in cerebrospinal fluid (CSF) secretion/absorption resulting in fluid accumulation within the brain with consequential pathophysiology. Our research has identified a unique cerebral folate system in which depletion of CSF 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is associated with cortical progenitor cell-cycle arrest in hydrocephalic Texas (H-Tx) rats. We used tissue culture, immunohistochemistry, in-situ PCR and RT-PCR and found that the in-vitro proliferation of arachnoid cells is highly folate-dependent with exacerbated proliferation occurring in hydrocephalic CSF that has low FDH but high folate-receptor-alpha (FRα) and folate. Adding FDH to this CSF prevented aberrant proliferation indicating a regulatory function of FDH on CSF folate concentration. Arachnoid cells have no detectable mRNA for FRα or FDH, but FDH mRNA is found in the choroid plexus (CP) and CSF microvesicles. Co-localization of FDH, FRα and folate suggests important functions of FDH in cerebral folate transport, buffering and function. In conclusion, abnormal CSF levels of FDH, FRα and folate inhibit cortical cell proliferation but allow uncontrolled arachnoid cell division that should increase fluid absorption by increasing the arachnoid although this fails in the hydrocephalic brain. FDH appears to buffer available folate to control arachnoid proliferation and function.

scholarly journals Lymphocyte interleukin 2 production and responsiveness are altered in patients with primary myelodysplastic syndrome

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 494-500
Author(s):  
O Ayanlar-Batuman ◽  
J Shevitz ◽  
UC Traub ◽  
S Murphy ◽  
D Sajewski
Keyword(s):  
T Cells ◽  
B Cells ◽  
Myelodysplastic Syndrome ◽  
B Cell ◽  
Interleukin 2 ◽  
T Cell Proliferation ◽  
Cell Functions ◽  
Normal Limits ◽  
Stimulatory Capacity

Immunoregulatory T and B cell functions in 15 patients with primary myelodysplastic syndrome (MDS) were studied by measuring the proliferative and the stimulatory capacity of T and B cells, respectively, in autologous (auto) and allogeneic (allo) mixed lymphocyte reaction (MLR). T cell proliferation in the auto MLR was 25% of the control (P less than .02), whereas proliferation in the allo MLR was normal. When control T cells were stimulated by MDS B cells, their proliferative response was only 57% of the control (P less than .01). The mechanism responsible for these abnormalities was studied by determining the capacity of MDS and normal T cells to produce interleukin 2 (IL 2) and to generate IL 2 receptors (IL 2R) following stimulation with control and MDS B cells. In the auto MLR of MDS patients, only 3% +/- 2% of T cells developed IL 2R positivity, whereas in control cultures 12% +/- 2% of T cells were positive, as determined by immunofluorescence, using a monoclonal antibody (MoAb) directed against the IL 2R, and FACS analysis. When MDS T cells were stimulated by control B cells, IL 2R generation and the production of IL 2 were within normal limits. In contrast, when control T cells were stimulated by MDS B cells or control B cells, the MDS B cells induced production of only 26% of IL 2 as compared with control B cells. In parallel experiments, IL 2R generation in control T cells stimulated by either MDS or control B cells was similar. We conclude that in the primary MDS, T and B cell interactions are impaired. Although MDS T cells develop normal quantities of IL 2R and produce normal amounts of IL 2 when stimulated by control B cells, they are markedly impaired when stimulated by self B cells. Similarly, MDS B cells can induce IL 2R generation in control T cells but not in MDS T cells. Myelodysplastic B cells are also defective in inducing IL 2 production by normal T cells in an allo MLR. These in vitro abnormalities strongly suggest that generation of lymphocytes with immunoregulatory functions is impaired in patients with MDS.

Recipient immune-competent T lymphocytes can survive intensive conditioning for bone marrow transplantation

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 954-956 ◽  
Author(s):  
A Butturini ◽  
RC Seeger ◽  
RP Gale
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Lymphocytes ◽  
Graft Rejection ◽  
Marrow Transplantation ◽  
Interleukin 2 ◽  
Marrow Transplant ◽  
Effector Cells ◽  
And Function

Abstract Bone marrow transplantation is usually preceded by intensive chemotherapy and radiation therapy designed to completely eliminate recipient immune-competent cells that might reject the donor bone marrow. We show that seven of 14 bone marrow transplant recipients who received intensive conditioning retained circulating T lymphocytes that proliferate after incubation with interleukin 2 and phytohemagglutinin and function as effector cells in an in vitro model of graft rejection. These T cells may mediate graft rejection.

Circulating CD24hiCD38hi regulatory B cells correlate inversely with the ThEM17 cell frequency in granulomatosis with polyangiitis patients

Rheumatology ◽  
2019 ◽  
Vol 58 (8) ◽  
pp. 1361-1366 ◽  
Author(s):  
Anouk von Borstel ◽  
Lucas L Lintermans ◽  
Peter Heeringa ◽  
Abraham Rutgers ◽  
Coen A Stegeman ◽  
...  
Keyword(s):  
B Cells ◽  
Granulomatosis With Polyangiitis ◽  
Cultured Cells ◽  
Effector Memory ◽  
Regulatory B Cells ◽  
Cell Frequency ◽  
Th1 Cell ◽  
Th Cells ◽  
Cpg Oligodeoxynucleotides

Abstract Objectives To investigate whether there is a direct relation between expanded proportions of Th17 effector memory (ThEM17) cells and regulatory B cells (Bregs) in peripheral blood of granulomatosis with polyangiitis (GPA) patients. Methods Frequencies of Bregs and ThEM17 cells, as well as ThEM1 cells, were determined by flow cytometry in blood samples from 42 GPA patients in remission and 18 matched healthy controls (HCs). The Breg frequency was defined as CD24hiCD38hiCD19+ cells. ThEM17 cells were defined as CCR6+CXCR3-CCR4+ cells and ThEM1 cells as CCR6-CXCR3+CCR4- cells within the CD3+CD4+CD45RO+CCR7- population. In addition, CD3+CD4+ Th cells from 9 GPA patients were co-cultured in vitro with either total B cells or a Breg-depleted B cell fraction. Cultured cells were stimulated with Staphylococcus Enterotoxin B (SEB) and CpG-oligodeoxynucleotides (CpG-ODN). Th17- (IL-17+) and Th1 cell (IFNγ+) frequencies were determined at baseline and day 5 upon restimulation with phorbol myristate acetate (PMA) and Ca-I. Results A decreased Breg frequency was found in treated GPA patients, whereas an increased ThEM17 cell frequency was observed in treated and untreated GPA patients compared with HCs. Additionally, a decreased ThEM1 cell frequency was seen in untreated GPA patients compared with HCs. In untreated GPA patients circulating Breg frequencies correlated negatively with ThEM17 cells (r = −0.533; P = 0.007) and positively with ThEM1 cells (r = −0.473; P = 0.015). The co-culture experiments revealed a significant increase in the frequency of IL-17+ Th cells in Breg-depleted samples (median: 3%; range: 1–7.5%) compared with Breg-undepleted samples (P = 0.002; undepleted samples median: 2.1%; range: 0.9–6.4%), whereas no difference in the frequency of IFNγ+ Th cells in Breg-depleted cultures was observed (undepleted median: 11.8%; range: 2.8–21% vs Breg-depleted median: 12.2%; range: 2.6–17.6%). Conclusion Bregs modulate ThEM17 responses in GPA patients. Future studies should elaborate on clinical and therapeutical implications of the Breg-Th17 interaction in GPA patients.

scholarly journals gamma-c gene transfer into SCID X1 patients' B-cell lines restores normal high-affinity interleukin-2 receptor expression and function

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3108-3116 ◽  
Author(s):  
H Hacein-Bey ◽  
M Cavazzana-Calvo ◽  
F Le Deist ◽  
A Dautry-Varsat ◽  
C Hivroz ◽  
...  
Keyword(s):  
B Cells ◽  
Gene Transfer ◽  
B Cell ◽  
Cell Lines ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Receptor Expression ◽  
Chain Gene ◽  
High Affinity ◽  
And Function

SCID X1 is characterized by faulty T-cell and natural killer cell differentiation caused by mutation of the gamma-c chain gene encoding a number of multiple cytokine receptors (interleukin-2 [IL-2], IL-4, IL- 7, IL-9, and IL-15 receptors). To assess the feasibility of inducing long-term expression and function of the gamma-c chain, Epstein-Barr virus (EBV)-transformed B-cell lines from two patients with SCID X1 were transduced with a Moloney-derived retroviral vector containing the gamma-c chain cDNA. The viral LTR was used as the promoter. Immediately after two cycles of coculture with the psi-crip clone producing the MFG(B2)-gamma-c cDNA vector, gamma-c expression, assessed by detection of the mRNA and membrane protein expression, was found in 15% to 20% of cells. The degree of membrane expression was similar to that in control EBV-B cells. Expression increased steadily over 6 months, becoming detectable in 100% of cells, and remained stable thereafter for a total of 9 months, reflecting positive selection of transduced cells. A study of provirus integration sites showed multiple integration. The expressed gamma-c was functional, because it restored high-affinity IL- 2 receptor binding, IL-2 endocytosis, and IL-2-triggered phosphorylation of JAK-3 tyrosine kinase. Similar results were obtained with the two B-cell lines. These results show that efficient gamma-c gene transfer into B-cells lacking functional gamma-c is feasible and results in strong and stable expression of a functional gamma-c chain, apparently conferring a selective growth advantage in culture. Further in vitro studies of gamma-c gene transfer into gamma-c- hematopoietic progenitors are being conducted to assess the feasibility of correcting lymphocyte differentiation defects.

scholarly journals BCL-6 expression during B-cell activation

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5257-5268 ◽  
Author(s):  
D Allman ◽  
A Jain ◽  
A Dent ◽  
RR Maile ◽  
T Selvaggi ◽  
...  
Keyword(s):  
B Cells ◽  
T Lymphocytes ◽  
Germinal Center ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Large Cell ◽  
Cd40 Ligand ◽  
Mrna Levels ◽  
Coding Region

Translocations involving the BCL-6 gene are common in the diffuse large cell subtype of non-Hodgkin's lymphoma. Invariably, the BCL-6 coding region is intact, but its 5′ untranslated region is replaced with sequences from the translocation partner. The present study shows that BCL-6 expression is regulated in lymphocytes during mitogenic stimulation. Resting B and T lymphocytes contain high levels of BCL-6 mRNA. Stimulation of mouse B cells with anti-IgM or IgD antibodies, bacterial lipopolysaccharide, phorbol 12-myristate 13-acetate plus ionomycin, or CD40 ligand led to a five-fold to 35-fold decrease in BCL-6 mRNA levels. Similar downregulation of BCL-6 mRNA was seen in human B cells stimulated with Staphylococcus aureus plus interleukin-2 or anti-IgM antibodies and in human T lymphocytes stimulated with phytohemagglutinin. BCL-6 mRNA levels began to decrease 8 to 16 hours after stimulation, before cells entered S phase. Although polyclonal activation of B cells in vitro invariably decreased BCL-6 MRNA expression, activated B cells from human germinal centers expressed BCL-6 mRNA at levels comparable to the levels in resting B cells. Despite these similar mRNA levels, BCL-6 protein expression was threefold to 34-fold higher in germinal center B cells than in resting B cells, suggesting that BCL-6 protein levels are controlled by translational or posttranslational mechanisms. These observations suggest that the germinal center reaction provides unique activation signals to B cells that allow for continued, high-level BCL-6 expression.

scholarly journals Telomerase Activity Is Induced in Human Peripheral B Lymphocytes by the Stimulation to Antigen Receptor

Blood ◽  
1997 ◽  
Vol 89 (4) ◽  
pp. 1299-1307 ◽  
Author(s):  
Hideya Igarashi ◽  
Nobuo Sakaguchi
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Antigen Receptor ◽  
Telomerase Activity ◽  
B Cell Activation ◽  
Molecular Events

Abstract To understand the molecular events for the proliferation of B cells, we studied the induction of telomerase activity in vitro after stimulation to B-cell antigen receptor (BCR) on human peripheral B cells. Although unstimulated purified B cells of tonsils and peripheral blood from healthy volunteers do not express detectable telomerase activity, anti-IgM beads induce telomerase activity in these B cells. Soluble anti-IgM antibody (Ab) alone does not induce telomerase activity, but the second signal, given by either one of the cytokines of interleukin-2 (IL-2), IL-4, and IL-13 or by anti-CD40 monoclonal Ab (MoAb), is effective as the costimulation for the induction of the activity. Stimulation with antiIgM Ab and anti-CD40 MoAb induces telomerase activity in most mature B cells of the tonsils and peripheral blood. The stimuli to both IgM and IgD receptors similarly induce the activity. Induction of telomerase activity is accompanied with the proliferation of B cells, but is not absolutely correlated with the extent of B-cell growth. Phorbol dibutylate (PDB) plus calcium (Ca) ionophore (PDB/Ca), which replace the activation through BCR and the costimulatory molecules, also induce telomerase activity. Moreover, it is suggested that phosphoinositide (PI) 3-kinase plays a role for the induction of telomerase activity in B cells stimulated with anti-IgM Ab and anti-CD40 MoAb. These results suggest that telomerase activity is induced in the B-cell activation of the antigen specific immune response.

scholarly journals Autophosphorylation of Tyr397 and its phosphorylation by Src-family kinases are altered in focal-adhesion-kinase neuronal isoforms

2000 ◽  
Vol 348 (1) ◽  
pp. 119-128 ◽  
Author(s):  
Madeleine TOUTANT ◽  
Jeanne-Marie STUDLER ◽  
Ferran BURGAYA ◽  
Alicia COSTA ◽  
Pascal EZAN ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Fluorescent Protein ◽  
Focal Adhesions ◽  
Src Family Kinases ◽  
Critical Residue ◽  
Green Fluorescent ◽  
And Function

In brain, focal adhesion kinase (FAK) is regulated by neurotransmitters and has a higher molecular mass than in other tissues, due to alternative splicing. Two exons code for additional peptides of six and seven residues (‘boxes’ 6 and 7), located on either side of Tyr397, which increase its autophosphorylation. Using in situ hybridization and a monoclonal antibody (Mab77) which does not recognize FAK containing box 7, we show that, although mRNAs coding for boxes 6 and 7 have different patterns of expression in brain, FAK+6,7 is the main isoform in forebrain neurons. The various FAK isoforms fused to green fluorescent protein were all targeted to focal adhesions in non-neuronal cells. Phosphorylation-state-specific antibodies were used to study in detail the phosphorylation of Tyr397, a critical residue for the activation and function of FAK. The presence of boxes 6 and 7 increased autophosphorylation of Tyr397 independently and additively, whereas they had a weak effect on FAK kinase activity towards poly(Glu,Tyr). Src-family kinases were also able to phosphorylate Tyr397 in cells, but this phosphorylation was decreased in the presence of box 6 or 7, and abolished in the presence of both. Thus the additional exons characteristic of neuronal isoforms of FAK do not alter its targeting, but change dramatically the phosphorylation of Tyr397. They increase its autophosphorylation in vitro and in transfected COS-7 cells, whereas they prevent its phosphorylation when co-transfected with Src-family kinases.

scholarly journals Interleukin-13 inhibits interleukin-2-induced proliferation and protects chronic lymphocytic leukemia B cells from in vitro apoptosis

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 1022-1029 ◽  
Author(s):  
N Chaouchi ◽  
C Wallon ◽  
C Goujard ◽  
G Tertian ◽  
A Rudent ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Interleukin 2 ◽  
Intermediate Stage ◽  
Lymphocytic Leukemia ◽  
Spontaneous Apoptosis ◽  
Interleukin 13 ◽  
B Cell Maturation ◽  
Cd23 Expression

Human interleukin-13 (IL-13) acts at different stages of the normal B- cell maturation pathway with a spectrum of biologic activities overlapping those of IL-4. B chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of slow-dividing and long-lived monoclonal B cells, arrested at the intermediate stage of their differentiation. In vitro, B-CLL cells exhibit a spontaneous apoptosis regulated by different cytokines. In this report, we show that IL-13 (10 to 200 ng/mL) acts directly on monoclonal B-CLL cells from 12 patients. (1) IL-13 enhances CD23 expression and induces soluble CD23 secretion by B-CLL cells but does not exhibit a growth factor activity. (2) IL-13 inhibits IL-2 responsiveness of B-CLL cells, activated either with IL-2 alone or through crosslinking of lgs or ligation of CD40 antigen. (3) IL-13 protects B-CLL cells from in vitro spontaneous apoptosis. The effects of IL-13 on neoplasic B cells were slightly less than those of IL-4 and occurred independently of the presence of IL-4. The present observations show that IL-13 may exhibit a negative regulatory effect on neoplasic B cells in contrast with that observed in normal B cells, and suggest that IL-13 could be an important factor in the pathogenesis of CLL by preventing the death of monoclonal B cells. Moreover, B-CLL may be an interesting model to study the regulation of the expression of IL-13 receptor and/or signal transduction pathways.

scholarly journals IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2409-2414 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Steven A. Rosenberg
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Selective Inhibition ◽  
High Dose ◽  
Protein Levels ◽  
And Function ◽  
The Impact

Abstract Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+CD25hi T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+CD25hi T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+CD25hi T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+CD25hi Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration. (Blood. 2006;107:2409-2414)

Sign in / Sign up

Export Citation Format

Share Document