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 A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

1998 ◽  
Vol 188 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
Mark H. Kaplan ◽  
Andrea L. Wurster ◽  
Michael J. Grusby
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Signal Transducer ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

scholarly journals Regulatory B cells (Bregs) inhibit osteoclastogenesis and prevent bone loss in osteoporotic mice model

2021 ◽  
Author(s):  
Leena Sapra ◽  
Asha Bhardwaj ◽  
Pradyumna K. Mishra ◽  
Bhupendra K. Verma ◽  
Rupesh K. Srivastava
Keyword(s):  
B Cells ◽  
Bone Marrow Cells ◽  
Dependent Manner ◽  
Regulatory B Cells ◽  
Mice Model ◽  
Post Menopausal Osteoporosis ◽  
Post Menopausal ◽  
First Time

AbstractIncreasing evidences in recent years have suggested that regulatory B cells (Bregs) are crucial modulator in various inflammatory disease conditions. However, the role of Bregs in case of postmenopausal osteoporosis remains unknown. Also, no study till date have ever investigated the significance of Bregs in modulating osteoclastogenesis. In the present study, we for the first time examined the anti-osteoclastogenic potential of Bregs under in vitro conditions and we observed that Bregs suppressed RANKL mediated osteoclastogenesis in bone marrow cells in a dose dependent manner. We further elucidated the mechanism behind the suppression of osteoclasts differentiation by Bregs and found that Bregs inhibit osteoclastogenesis via IL-10 production. To further confirm the bone health modulating potential of Bregs we employed post-menopausal osteoporotic mice model. Remarkably, our in vivo data clearly suggest a significant reduction (p < 0.01) in both CD19+IL-10+ and CD19+CD1dhiCD5+IL-10+ B10 Bregs in case of osteoporotic mice model. Moreover, our serum cytokine data further confirms the significant reduction of IL-10 levels in osteoporotic mice. Taken together, the present study for the first time unravels and establish the unexplored role of regulatory B cells in case of osteoporosis and provide new insight into Bregs biology in the context of post-menopausal osteoporosis.

scholarly journals Evidence for enhanced Bruton’s tyrosine kinase activity in transitional and naïve B cells of patients with granulomatosis with polyangiitis

Rheumatology ◽  
2019 ◽  
Vol 58 (12) ◽  
pp. 2230-2239
Author(s):  
Anouk von Borstel ◽  
Wayel H Abdulahad ◽  
Jan Stephan Sanders ◽  
Jasper Rip ◽  
Stefan F H Neys ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antibody Production ◽  
Granulomatosis With Polyangiitis ◽  
Cytokine Production ◽  
B Cell Subsets ◽  
Auto Antibody ◽  
Subset Distribution ◽  
Cell Cytokine Production

Abstract Objectives To determine Bruton’s tyrosine kinase (BTK) protein and phosphorylation levels in B cell subsets of granulomatosis with polyangiitis (GPA) patients and to investigate the effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production. Methods BTK protein and phosphorylation levels were determined by flow cytometry in peripheral blood B cells of 29 untreated GPA patients [9 active and 20 remission GPA patients (10 ANCA– and 10 ANCA+)], 9 age- and sex-matched healthy controls (HCs) and 9 untreated active RA patients. The effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production was determined in the same donors in peripheral blood mononuclear cell cultures. Results BTK protein levels were significantly increased in transitional and naïve B cells of active GPA and RA patients compared with remission GPA patients and HCs. Both B cell subsets of active patients were more sensitive to B cell receptor stimulation, as BTK and phospholipase Cγ2 phosphorylation were increased in these patients. In vitro BTK blockade had profound effects on B cell cytokine production, plasma cell formation and (auto)antibody production in both GPA patients and HCs. Interestingly, the effect of BTK blockade was less pronounced in active GPA patients, possibly due to increased activation of B cells. Conclusion We show that BTK protein and phosphorylation levels are most profoundly increased in newly emerging B cells of active GPA patients compared with remission patients. BTK blockade greatly inhibits in vitro B cell effector functions in GPA patients and HCs. These promising data identify BTK as an interesting novel therapeutic target in the treatment of GPA.

In Vitro Co-Culture of CLL-B Cells Reveals Long-Term Survival, Proliferation, and Maintenance of Telomere Length

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 350-350
Author(s):  
Ceri H Jones ◽  
Thet Thet Lin ◽  
Elisabeth Jane Walsby ◽  
Guy E Pratt ◽  
Christopher Fegan ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Telomere Length ◽  
Erosion Rate ◽  
Ex Vivo ◽  
Effector Memory ◽  
Long Term Culture

Abstract Telomere length is a prognostic factor in Chronic Lymphocytic Leukemia (CLL) with short telomere length a powerful predictor of early time to first treatment and reduced overall survival. However, little is known about telomere dynamics through the course of an individual patient's disease. Our recent longitudinal analysis of CLL B-cell telomere length revealed very little dynamic change within individual patients with a mean erosion rate of -52bp/year (p=0.05). In marked contrast, T-cells derived from the same patients showed a significantly higher mean erosion rate of -119bp/year (p=0.02) with a median follow up time of 69 months. Here we present data derived from long-term in-vitro co-culture of peripheral blood from CLL patients coupled with temporal analysis of their telomere length dynamics. We utilized a multi-cellular co-culture system, comprised of autologous T-cells and CD40L-expressing mouse fibroblasts, to maintain CLL cells in long-term culture. Patient-derived peripheral blood mononuclear cells (n=16) were maintained for a median of 70 days (range 54-154); samples were analyzed every two weeks for tumor cell telomere length and evidence of proliferation. We used fluorescence-activated cell sorting (FACS) to sort populations of CD19+CD5+ CLL B-cells and CD3+ T-cells from each of the cultures. We then performed high-resolution single telomere length analysis (STELA) on these sorted subsets of cells and analyzed their telomere dynamics over this extended time course. Analysis of CLL B-cells from these cultures revealed significantly increased Ki-67+ at day 14 when compared to day 0 (p<0.001) and this was evident for the duration of the cultures. Despite sustained tumor cell proliferation, we observed no significant difference in the CLL B-cell telomere length with a mean TL at the start of 4.5kb vs 4.3kb at the end (p=0.14). The presence of T-cells was shown to be critical for the maintenance of the long-term cultures in two ways. Firstly, cultures that were treated with 4μM fludarabine showed a catastrophic reduction in T-cells (p=0.01), which was associated with a significantly shorter duration of survival of CLL B-cells when compared to untreated controls (median 17.5 days (range 7-70); p<0.001). Secondly, it proved impossible to maintain T-cell depleted, purified CLL B-cells, in long-term culture. T-cells isolated from the long-term cultures showed evidence of proliferation with Ki-67+ again being increased at day 14 in comparison to baseline (p=0.003). Furthermore, T-cells derived from these cultures showed a significant alteration in subset composition over time with a decrease in the numbers of naive CD4+ (p=0.05) and CD8+ (p=0.02) T-cells and a corresponding increase in effector memory (p=0.2) and terminally differentiated effector memory (EMRA) subsets (p=0.07). In conclusion, this study demonstrates that we have developed a robust, long-term culture method for the maintenance of CLL cells. Despite evidence of sustained CLL proliferation, CLL B-cells showed little telomere length erosion during long-term co-culture and this is compatible with our recent ex-vivo analysis, which showed that the telomere length of CLL B-cells are remarkably stable with a mean erosion rate of only -52bp/year. In both ex-vivo and in-vitro analysis, telomere erosion correlated with starting telomere length (r2=0.14, p=0.04 and r2=0.3 p=0.03 respectively). Taken together, our in-vitro and ex-vivo data imply that the radically short telomeres observed in some CLL patients are not the result of increased proliferation of the malignant B-cell, but rather the mutagenic event occurs in a B-cell which already has short telomeres. Furthermore, our novel long-term culture model has reinforced the vital role of T-cells in sustaining CLL B-cells viability and proliferation in-vitro. Given the consistent skewing of the T-cell pool towards a memory phenotype it seems unlikely that this is driven in-vitro by cognate TCR antigen recognition but rather a cytokine-mediated response. Disclosures Fegan: Gilead Sciences: Honoraria; Roche: Honoraria; AbbVie: Honoraria.

scholarly journals Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells.

1994 ◽  
Vol 179 (2) ◽  
pp. 425-438 ◽  
Author(s):  
M P Cooke ◽  
A W Heath ◽  
K M Shokat ◽  
Y Zeng ◽  
F D Finkelman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
B Lymphocytes ◽  
Molecular Mechanisms ◽  
Interleukin 4 ◽  
Th Cells

The specificity of antibody (Ab) responses depends on focusing helper T (Th) lymphocyte signals to suitable B lymphocytes capable of binding foreign antigens (Ags), and away from nonspecific or self-reactive B cells. To investigate the molecular mechanisms that prevent the activation of self-reactive B lymphocytes, the activation requirements of B cells specific for the Ag hen egg lysozyme (HEL) obtained from immunoglobulin (Ig)-transgenic mice were compared with those of functionally tolerant B cells isolated from Ig-transgenic mice which also express soluble HEL. To eliminate the need for surface (s)Ig-mediated Ag uptake and presentation and allow the effects of sIg signaling to be studied in isolation, we assessed the ability of allogeneic T cells from bm12 strain mice to provide in vivo help to C57BL/6 strain-transgenic B cells. Interestingly, non-tolerant Ig-transgenic B cells required both allogeneic Th cells and binding of soluble HEL for efficient activation and Ab production. By contrast, tolerant self-reactive B cells from Ig/HEL double transgenic mice responded poorly to the same combination of allogeneic T cells and soluble HEL. The tolerant B cells were nevertheless normally responsive to stimulation with interleukin 4 and anti-CD40 Abs in vitro, suggesting that they retained the capacity to respond to mediators of T cell help. However, the tolerant B cells exhibited a proximal block in the sIg signaling pathway which prevented activation of receptor-associated tyrosine kinases in response to the binding of soluble HEL. The functional significance of this sIg signaling defect was confirmed by using a more potent membrane-bound form of HEL capable of triggering sIg signaling in tolerant B cells, which markedly restored their ability to collaborate with allogeneic Th cells and produce Ab. These findings indicate that Ag-specific B cells require two signals for mounting a T cell-dependent Ab response and identify regulation of sIg signaling as a mechanism for controlling self-reactive B cells.

Direct Growth Inhibition of Both Mouse and Human B Cell Lymphomas by CpG Oligodeoxynucleotides

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2854-2854
Author(s):  
Reiko E Yamada ◽  
David J Betting ◽  
Michael Ahdoot ◽  
Kristopher K Steward ◽  
John M Timmerman
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Cpg Oligodeoxynucleotides ◽  
Mantle Cell ◽  
Class B ◽  
Human B Cell

Abstract Abstract 2854 Immunostimulatory CpG oligodeoxynucleotides (ODN) are potent activators of T cell immunity and antibody-dependent cellular cytotoxicity (ADCC), and under study as immunotherapeutic agents for a variety of cancers, including B cell lymphomas. Recently, anti-CD20 antibody-CpG conjugates have been shown to eradicate rituximab-resistant B cell lymphoma in a syngeneic murine lymphoma model (D. Betting et al, ASH 2009). CpG is known to strongly stimulate the proliferation of normal B cells. Paradoxically, CpG has been reported to markedly inhibit the in vitro growth of the murine B cell lymphoma A20 (J. Li et al, J. Immunol. 2007), thereby prompting us to investigate the direct effects of CpGs on the growth of human B cell lymphomas. We first demonstrated that CpGs, especially those of the B class, potently inhibited proliferation of the A20 mouse B cell line in vitro by up to 81.5% (class A 58.7% and class C 52.7%). Moreover, in non-tumor bearing mice intratumoral injections of CpG activated normal B cells, while mice bearing subcutaneous A20 tumors showed suppressed tumor growth after CpG injections. Similarly, in humans, CpGs strongly stimulated the proliferation of normal peripheral blood B cells (stimulation index for class B 27.5 at 5 μg/ml). A panel of 12 human lymphoma cell lines (DLBCL, Burkitt's, mantle cell) were cultured in the presence or absence of varying concentrations of CpGs of A, B, or C classes (50, 10, or 2 μg/ml) or control ODN. Proliferation was measured by [3H]-thymidine incorporation in quadruplicate 72 hour cultures, and apoptosis measured by Annexin-V and PI flow cytometry. In contrast to the stimulation observed with normal human B cells, the proliferation of all 12 lymphoma lines were inhibited by CpGs. The strongest inhibitory effects were seen with CpG 7909, a class B CpG under clinical development for cancer therapy (Pfizer, PF-3512676). Raji cells were inhibited by 77.9%, 40.7%, and 8.8% at CpG concentrations of 50, 10, and 2 μg/ml, respectively (p≤0.01 for all comparisons vs. media alone). Among the 12 tested cell lines, the percentage growth inhibition using 50 μg/ml CpG 7909 was 61.2–80.4% for germinal center-type DLBCL (SUDHL-4, SUDHL-6, OCI-Ly19), 50–59.5% for activated B cell-type DLBCL (SUDHL-2, OCI-Ly3, OCI-Ly10), 56.4–79.3% for Burkitt's lymphomas (Raji, Ramos, Daudi, BJAB), and 69.6–69.9% for mantle cell lymphomas (Jeko-1, Granta-519). Interestingly, although all of the human cell lines expressed TLR9 by semi-quantitative RT-PCR, inhibition in the proliferation levels did not correlate with TLR9 expression levels. CpG 7909 also induced significant levels of apoptosis in Raji and Jeko-1 cells, 10.1% and 27.6% respectively at 50 μg/ml. In conclusion, we have demonstrated that CpGs have divergent effects on normal versus malignant B cells in both mouse and human systems. Delivery of CpG to mouse lymphoma cells inhibited their growth in vivo, while normal mouse B cells were activated. Furthermore, CpGs directly inhibit the proliferation of a large panel of human B cell lymphomas representing the majority of aggressive histologies. These results provide a novel mechanism of action for CpGs as therapeutic agents for B cell lymphomas. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus.

1993 ◽  
Vol 177 (5) ◽  
pp. 1367-1381 ◽  
Author(s):  
C Mohan ◽  
S Adams ◽  
V Stanik ◽  
S K Datta
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Autoimmune Response ◽  
Th Cells ◽  
Variable Regions ◽  
Peptide Epitopes ◽  
Autoreactive T Cell

Only a fraction (12%) of 268 "autoreactive" T cell clones derived from lupus-prone mice can selectively induce the production of pathogenic anti-DNA autoantibodies in vitro and accelerate the development of lupus nephritis when transferred in vivo. The CDR3 loops of T cell receptor beta chains expressed by these pathogenic T helper (Th) clones contain a recurrent motif of anionic residues suggesting that they are selected by autoantigens with cationic residues. Herein, we found that approximately 50% of these pathogenic Th clones were specific for nucleosomal antigens, but none of them responded to cationic idiopeptides shared by variable regions of pathogenic anti-DNA autoantibodies. Nucleosomes did not stimulate the T cells as a nonspecific mitogen or superantigen. Only the pathogenic Th cells of lupus responded to nucleosomal antigens that were processed and presented via the major histocompatibility class II pathway. Although the presentation of purified mononucleosomes to the Th clones could be blocked by inhibitors of endosomal proteases, neither of the two components of the nucleosomes--free DNA or histones by themselves--could stimulate the Th clones. Thus critical peptide epitopes for the Th cells were probably protected during uptake and processing of the nucleosome particle as a whole. The nucleosome-specific Th clones preferentially augmented the production of IgG autoantibodies to histone-DNA complex in vitro. In vivo, nucleosome-specific, CD4+ T cells were not detectable in normal mice, but they were found in the spleens of lupus-prone mice as early as 1 mo of age, long before other autoimmune manifestations. Immunization of young, preautoimmune lupus mice with nucleosomes augmented the production of autoantibodies and markedly accelerated the development of severe glomerulonephritis. Previously, crude preparations containing nucleosomes were shown by others to have polyclonal mitogenic activity for B cells from normal as well as lupus mice. Identification here of pure mononucleosome as a lupus-specific immunogen for the Th cells that selectively help the pathogenic anti-DNA autoantibody producing B cells of lupus could lead to the design of specific therapy against this pathogenic autoimmune response.

scholarly journals Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis.

1987 ◽  
Vol 165 (5) ◽  
pp. 1252-1268 ◽  
Author(s):  
S K Datta ◽  
H Patel ◽  
D Berry
Keyword(s):  
T Cells ◽  
B Cells ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Underlying Mechanism ◽  
Systemic Autoimmune Disease ◽  
Murine Models ◽  
Th Cells ◽  
Class B

We investigated the underlying mechanisms of systemic autoimmune disease in MRL-+/+, (NZB X NZW)F1, and (NZB X SWR)F1 mice, since these strains develop glomerulonephritis without the superimposition of any secondary lupus-accelerating genes. All three strains manifested a common immunoregulatory defect specific for the production of pathogenic anti-DNA autoantibodies that are of IgG class and cationic in charge. At or just before the age they began to develop lupus nephritis, spleen cells of the mice contained a subpopulation of Th cells that selectively induced their B cells in vitro to produce highly cationic IgG autoantibodies to both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). By contrast, T cells from younger preautoimmune mice were incapable of providing this help. Moreover, only B cells of the older lupus mice could be induced to secrete cationic anti-DNA antibodies of IgG class. B cells of young lupus mice could not produce the cationic autoantibodies even with the help of T cells from the older mice, nor upon stimulation with mitogens. In the older lupus mice we found two sets of Th cells that spontaneously induced the cationic shift in autoantibodies; one set belonged to the classical Th category with L3T4+,Lyt-2- phenotype, whereas the other surprisingly belonged to a double-negative (L3T4-,Lyt-2-), Lyt-1+ subpopulation. The latter set of unusual Th cells were unexpected in these lupus mice since they lacked the lpr (lympho-proliferation) gene. Thus three apparently different murine models of systemic lupus erythematosus possess a common underlying mechanism specific for the spontaneous production of pathogenic anti-DNA autoantibodies.

scholarly journals Subpopulations of B cells distinguished by cell surface expression of Ia antigens. Correlation of Ia and idiotype during activation by cloned Ia-restricted T cells.

1983 ◽  
Vol 158 (2) ◽  
pp. 265-279 ◽  
Author(s):  
K Bottomly ◽  
B Jones ◽  
J Kaye ◽  
F Jones
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Cell Activation ◽  
Cell Surface Expression ◽  
Th Cells ◽  
Th Cell ◽  
Ia Antigens

We have investigated in vitro the induction of antibody responses to phosphorylcholine (PC) by cloned T helper (Th) cell lines. The cloned Th cells are antigen specific, in this case ovalbumin (OVA), self-Ia recognizing, and induce antibody secretion only if the hapten, PC, is physically linked to the carrier (OVA) molecule. The plaque-forming cell (PFC) response generated in the presence of cloned Th cells is idiotypically diverse with 5-40% of the secreting B cells bearing the TEPC-15 (T15) idiotype. The interaction of the cloned Th cells and unprimed B cells requires recognition of B cell surface Ia glycoproteins for all B cells activated to secrete anti-PC antibody, whether they be T15-bearing or not. More importantly, however, effective interaction between a cloned Th cell and a B cell is determined by the quantity of B cell surface Ia glycoproteins. Our results indicate that quantitative differences in B cell surface Ia antigens are directly related to B cell activation by the cloned Th cell. The high Ia density B cells are most easily activated by cloned Th cells, and these appear to be mainly non-T15-bearing. These data suggest that the failure of cloned Th cells to effectively activate T15-bearing B cells in vitro may be due to the lower relative Ia density of these B cells and therefore to their inability to interact effectively with cloned Ia-recognizing Th cells. These results imply that monoclonal T cells may distinguish between T15-bearing and non-T15-bearing B cells based on their Ia density.

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.

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