Targeting STAT3 Signaling to Augment the Immunogenicity of B-Cell Lymphomas

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 708-708
Author(s):  
Hongwei Wang ◽  
F. Cheng ◽  
K. Wright ◽  
J. Tao ◽  
M. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Dna Binding ◽  
B Cell ◽  
Cd4 T Cells ◽  
Mutant Form ◽  
B Cell Lymphomas ◽  
Stat3 Signaling ◽  
Antigen Presenting

Abstract STAT3 signaling has emerged as a negative regulator of inflammatory responses in immune cells. In bone-marrow derived antigen-presenting cells (APCs), genetic or pharmacologic disruption of STAT3 led to inflammatory cells that effectively prime antigen-specific T-cell responses and restore the responsiveness of tolerized T-cells. In contrast, enhanced Stat3 activity in APCs resulted in increased production of the immunosuppressive cytokine IL-10 and induction of T-cell tolerance1. B-cell lymphomas being tumors derived from B-lymphocytes display intrinsic antigen-presenting capabilities. Augmentation of this APC function has been shown to result in effective anti-lymphoma immunity2. In this study we determined whether targeting Stat3 signaling might influence the intrinsic APC function of malignant B-cells and the responsiveness –or not- of antigen-specific CD4+ T-cells. First, we specifically block STAT3 signaling in A20 lymphoma B-cells by using a dominant negative variant of STAT3, Stat3b. Inhibition of STAT3 resulted in tumor cells capable not only of fully priming naïve antigen-specific CD4+T-cells but also able of restoring the responsiveness of tolerant T-cells from lymphoma bearing mice. Conversely, transfection of A20 B-cells with Stat3c, a constitutively activated mutant form of STAT3, led to T-cell unresponsiveness. Of note, manipulation of STAT3 in B cell tumors was associated with changes in the mRNA expression and protein levels of IL-10. Second, we evaluated the effects of two novel Stat3 inhibitors, CPA-7 (a platinum-containing compound that disrupts STAT3 DNA binding activity) and S3I-201 (inhibitor of Stat3:Stat3 complex formation and Stat3 DNA binding and transcriptional activities) in a murine model of Mantle Cell Lymphoma (MCL). In vitro treatment of FC-muMCL1 cells - derived from a tumor elicited in Em-Cyclin D1 transgenic mice- with increasing concentrations of either CPA-7 or S3I-201 resulted in an enhanced presentation of OVA-peptide to naïve CD4+ T-cells specific for a MHC class II restricted epitope of ovalbumin (OT-II cells). Indeed, these T-cells produce higher levels of IL-2 and IFN-gamma compared to anti-OVA T cells that encountered cognate antigen in untreated FC-muMCL1 cells. More importantly, MCL cells treated with CPA-7 restored the responsiveness of tolerized anti-OVA CD4+ T-cells. Finally, in vivo treatment of MCL-bearing mice with CPA-7 (5 mg/kg/iv given on days +21, +24 and +27 after tumor challenge) resulted in significant inhibition of p-Stat3 in malignant B-cells and augmentation of their APC function. Taken together, STAT3 signaling is involved in the regulation of the antigen-presenting capabilities of B-cell lymphomas and as such represents a novel molecular target to augment the immunogenicity of these tumors.

scholarly journals A quantitative analysis of antigen-presenting cell function: activated B cells stimulate naive CD4 T cells but are inferior to dendritic cells in providing costimulation.

1994 ◽  
Vol 180 (5) ◽  
pp. 1829-1840 ◽  
Author(s):  
D J Cassell ◽  
R H Schwartz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Quantitative Analysis ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Costimulatory Signals ◽  
Antigen Presenting ◽  
Activated B Cells

Ligation of CD28 on CD4 Th1 clones and freshly isolated mixtures of naive and memory CD4 T cells triggered their T cell receptors (TCR) is sufficient to induce the costimulatory signals necessary for interleukin 2 (IL-2) production by these cells. CTLA-4-reactive ligands expressed on antigen-presenting cells (APC) are critical in providing costimulatory signals to these T cell populations. We demonstrate that these activation characteristics apply equally to purified naive CD4 T cells. Because B cell blasts express CTLA-4-reactive ligands and high levels of adhesion and major histocompatibility complex class II molecules, they would be expected to engage both the TCR and CD28 and consequently stimulate IL-2 production by naive CD4 T cells. Using purified populations of cells in limiting dilution cultures, we have carried out a quantitative analysis of the interaction between naive CD4 T cells and either activated B or dendritic cells. We demonstrate that B cell blasts stimulate a high frequency of naive CD4 T cells. Slight differences in TCR signaling efficiency between the two APC types were observed. Even at optimal peptide concentrations, however, the amount of IL-2 made by individual T cells was fourfold lower in response to B cell blasts than to dendritic cells. This relative deficiency of activated B cells was due to their inability to optimally costimulate naive CD4 T cells.

scholarly journals Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutations

2016 ◽  
Vol 213 (11) ◽  
pp. 2413-2435 ◽  
Author(s):  
Yi Wang ◽  
Cindy S. Ma ◽  
Yun Ling ◽  
Aziz Bousfiha ◽  
Yildiz Camcioglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Cell Phenotype ◽  
Loss Of Function ◽  
Inborn Errors

Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell–intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients’ B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.

Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection

2021 ◽  
Vol 118 (46) ◽  
pp. e2108157118
Author(s):  
Kerstin Narr ◽  
Yusuf I. Ertuna ◽  
Benedict Fallet ◽  
Karen Cornille ◽  
Mirela Dimitrova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Memory B Cells ◽  
Type I ◽  
Clonal Deletion ◽  
Cell Immunity ◽  
B Cell Immunity

Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)–driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called “decimation,” of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I–driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell–intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell–mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell–based vaccination against persistent viral diseases.

scholarly journals T Cell Accumulation in B Cell Follicles Is Regulated by Dendritic Cells and Is Independent of B Cell Activation

2003 ◽  
Vol 197 (2) ◽  
pp. 195-206 ◽  
Author(s):  
Simon Fillatreau ◽  
David Gray
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Cell Accumulation ◽  
Antigen Presenting ◽  
Deficient Mice

We investigated the mechanism of CD4 T cell accumulation in B cell follicles after immunization. Follicular T cell numbers were correlated with the number of B cells, indicating B cell control of the niche that T cells occupy. Despite this, we found no role for B cells in the follicular migration of T cells. Instead, T cells are induced to migrate into B cell follicles entirely as a result of interaction with dendritic cells (DCs). Migration relies on CD40-dependent maturation of DCs, as it did not occur in CD40-deficient mice but was reconstituted with CD40+ DCs. Restoration was not achieved by the activation of DCs with bacterial activators (e.g., lipopolysaccharide, CpG), but was by the injection of OX40L–huIgG1 fusion protein. Crucially, the up-regulation of OX40L (on antigen-presenting cells) and CXCR-5 (on T cells) are CD40-dependent events and we show that T cells do not migrate to follicles in immunized OX40-deficient mice.

Cucurbitacins, a Family of Natural Compounds That Effectively Disrupt Stat3 Signaling in Antigen-Presenting Cells (APCs) Are Promising Agents To Overcome Tumor-Induced CD4+ T-Cell Tolerance.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1485-1485
Author(s):  
Fengdong Cheng ◽  
Hongwei Wang ◽  
Alfonso Suarez ◽  
Pedro Horna ◽  
Said Sebti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
Cd4 T Cells ◽  
Natural Compounds ◽  
Dual Inhibitor ◽  
Ifn Gamma ◽  
Stat3 Signaling ◽  
Cognate Antigen ◽  
Antigen Presenting

Abstract Signal transducer and activator of transcription 3 (Stat3) is a key mediator of several cytokines and growth factors signaling pathways. On myeloid cells, activation of Stat3 to its phosphorylated form (pStat3) has been shown to negatively regulate inflammatory responses. Recently, we have unambiguously demonstrated that Stat3 signaling in APCs also play a central role in the decision leading to immune activation versus immune tolerance of antigen-specific T-cells1. In spite of these advances, there is however a paucity of therapeutic strategies targeting this signaling pathway in immune cells. Using a high throughput cytoblot screening for phospho-Stat3 inhibition, we have recently identified a family of natural compounds known as Cucurbitacins that effectively disrupt Stat3 signaling at different levels2. Three compounds have been identified, Cucurbitacin A (CuA) that inhibits phospho-JAK-2, Cucurbitacin I (CuI) a dual inhibitor of p-JAK2 and p-Stat3 and Cucurbitacin Q (CuQ) a selective inhibitor of p-Stat3. In vitro treatment of peritoneal elicited macrophages (PEM) and bone marrow-derived dendritic cells (DCs) with increasing concentrations of CuA or CuI resulted in inhibition of p-Stat3 and enhanced antigen presentation to naive CD4+ T cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA). Indeed, these clonotypic T cells displayed increased antigen-specific proliferation and IL-2 production as compared to clonotypic T cells encountering cognate antigen on untreated APCs. Furthermore, unlike untreated PEM or DCs, which are unable to trigger IFN-gamma production by CD4+ T-cells, Cucurbitacin-treated APCs efficiently trigger the production of this cytokine by naïve CD4+ T-cells in response to cognate antigen. Given the above results, we explored next whether inhibition of Stat3 signaling in B-cell lymphomas by Cucurbitacins might increase the intrinsic antigen-presenting capabilities of these malignant B-cells. Reminiscent of our findings with bone marrow derived APCs, Cucurbitacin-treated A20 lymphoma cells also display enhanced antigen-presenting cell function leading to increased proliferation, IL-2 and IFN-gamma by naive antigen-specific CD4+ T-cells. More importantly, tolerant CD4+ T-cells (isolated from lymphoma bearing mice) exposed to Cucurbitacin-treated A20 B-cells regained their ability to proliferate and produce significant amounts of IL-2 and IFN-gamma in response to cognate antigen stimulation. Taken together, the ability of Cucurbitacins to inhibit p-Stat3 in normal APCs as well as in malignant B-cells make these natural compounds a promising agents to overcome the remarkable barrier that tolerance to tumor antigens has imposed to cancer immunotherapeutic strategies.

Donor B Cells in Transplants Augment Clonal Expansion and Persistence of Pathogenic Donor CD4+ T Cells in Autoimmune-Like Chronic Graft-Versus-Host Disease,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4021-4021
Author(s):  
James Sundblom Young ◽  
Tao Wu ◽  
Yuhong Chen ◽  
Dongchang Zhao ◽  
Heather F Johnston ◽  
...  
Keyword(s):  
T Cells ◽  
Salivary Gland ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Graft Versus Host Disease ◽  
Tissue Damage ◽  
Cd4 T Cells ◽  
Clonal Expansion ◽  
Graft Versus Host

Abstract Abstract 4021 Chronic graft-versus-host disease (cGVHD) manifests with autoimmune symptoms (i.e. increased serum levels of autoantibodies, donor T cell infiltration in skin and salivary gland tissues, and collagen deposition in skin tissues). Donor B cells have been indicated to play an important role in the pathogenesis of cGVHD in mouse models as well as in patients, but the mechanisms remain unclear. In the current studies, using a cGVHD mouse model of DBA/2 donor to MHC-matched BALB/c host, we have observed that donor B cells are activated by donor CD4+ T cells in transplants to upregulate MHC II and co-stimulatory molecules and produce IgG autoantibodies; in turn, donor B cells mediated clonal expansion of autoreactive donor-type CD4+ T cells, as judged by TCR spectratyping and in vitro T cell proliferation in response to donor- and host-type APCs. Kinetic studies showed that the presence of donor B cells in transplants was associated with persistence of GVHD target tissue damage (i.e. sclerodermatous skin) and persistence of donor CD4+ T infiltration in the tissues in which there is an expansion of Th1 and Th2 but not Th17. The presence of donor B cells in transplants also markedly augmented tissue damage in prototypical cGVHD targets such as the salivary gland. Sorted donor CD4+ T cells from primary recipients given donor B cell-containing transplants but not from the primary recipients given B cell-depleted transplants caused cGVHD-like tissue damage in the skin and salivary gland of adoptive recipients. These results indicate that donor B cells in bone marrow transplants play an important role in the generation and expansion of pathogenic CD4+ T cells that mediate chronic GVHD tissue damage. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Antigen presentation by resting B cells. Radiosensitivity of the antigen-presentation function and two distinct pathways of T cell activation.

1984 ◽  
Vol 159 (3) ◽  
pp. 881-905 ◽  
Author(s):  
J D Ashwell ◽  
A L DeFranco ◽  
W E Paul ◽  
R H Schwartz
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
B Cell Activation ◽  
Antigen Presenting

In this report we have examined the ability of small resting B cells to act as antigen-presenting cells (APC) to antigen-specific MHC-restricted T cells as assessed by either T cell proliferation or T cell-dependent B cell stimulation. We found that 10 of 14 in vitro antigen-specific MHC-restricted T cell clones and lines and three of four T cell hybridomas could be induced to either proliferate or secrete IL-2 in the presence of lightly irradiated (1,000 rads) purified B cells and the appropriate foreign antigen. All T cell lines and hybridomas were stimulated to proliferate or make IL-2 by macrophage- and dendritic cell-enriched populations and all T cells tested except one hybridoma caused B cell activation when stimulated with B cells as APC. Furthermore, lightly irradiated, highly purified syngeneic B cells were as potent a source of APC for inducing B cell activation as were low density dendritic and macrophage-enriched cells. Lymph node T cells freshly taken from antigen-primed animals were also found to proliferate when cultured with purified B cells and the appropriate antigen. Thus, small resting B cells can function as APC to a variety of T cells. This APC function was easily measured when the cells were irradiated with 1,000 rads, but was greatly diminished or absent when they were irradiated with 3,300 rads. Thus, the failure of some other laboratories to observe this phenomenon may be the result of the relative radiosensitivity of the antigen-presenting function of the B cells. In addition, this radiosensitivity allowed us to easily distinguish B cell antigen presentation from presentation by the dendritic cell and macrophage, as the latter was resistant to 3,300 rads. Finally, one T cell clone that failed to proliferate when B cells were used as APC was able to recruit allogeneic B cells to proliferate in the presence of syngeneic B cells and the appropriate antigen. This result suggests that there are at least two distinct pathways of activation in T cells, one that leads to T cell proliferation and one that leads to the secretion of B cell recruitment factor(s).

Central T Cell Tolerance and Peripheral B Cell Tolerance for An RBC Autoantigen Are Incomplete in Healthy Mice; Implications for AIHA Pathogenesis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 693-693
Author(s):  
Krystalyn E Hudson ◽  
Jeanne Hendrickson ◽  
Chantel M Cadwell ◽  
Neal N Iwakoshi ◽  
James C. Zimring
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Peripheral Tolerance ◽  
Cd4 T Cell ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
B Cell Tolerance

Abstract Abstract 693 Introduction: Breakdown of humoral tolerance to red blood cell (RBC) antigens can result in autoimmune hemolytic anemia (AIHA), a severe and potentially fatal disease. The pathogenesis of AIHA is poorly understood. To investigate the baseline biology of tolerance to self-antigens expressed on RBCs, we utilized a murine transgenic mouse with RBC-specific expression of a model antigen consisting of a triple fusion protein of hen egg lysozyme (HEL), ovalbumin (Ova), and human blood group molecule Duffy; HEL-OVA-Duffy (HOD mouse). Methods: Wild-type C57BL/6 (B6) mice or HOD mice (on a B6 background) were immunized with HEL/CFA or OVA/CFA to test immune responses to antigens contained within HOD. Some animals were immunized with peptides as opposed to whole protein. Anti-HOD antibodies were quantified by indirect immunofluorescence using HOD RBCs as targets. Anti-HEL IgG was quantified by ELISA and anti-HEL secreting B cells were enumerated by ELISPOT. CD4+ T cell responses were assessed by tetramer staining and tetramer pull-down assays using I-Ab-OVA-329-337/326-334. T cell tolerance was specifically broken by adoptive transfer of OT-II CD4+ T cells into HOD mice (OT-II T cells recognize OVA323-339 presented by I-Ab). Effects of HOD antigen expression on B cell development were evaluated by crossing the HOD mouse with an anti-HEL BCR knockin mouse (SwHEL mouse) that is capable of normal class switching. Results: Immunization of B6 mice with OVA/CFA induced high titer antibodies reactive with HOD RBCs; in contrast, no anti-HOD was detected in HOD mice immunized with OVA/CFA. Similarly, no anti-HEL was detected in HOD mice immunized with HEL/CFA, whereas wild-type B6 mice had high anti-HEL titers (p<0.05). These data demonstrate overall humoral tolerance to the HOD antigen. Using pull-down assays, OVA-tetramer reactive T cells were detected in both B6 and HOD mice, with similar endogenous frequencies (mean numbers are 40 and 53 T cells, respectively; at least 6 mice analyzed), suggesting that central tolerance did not eliminate HOD reactive T cells. However, upon immunization with OVA peptide, B6 but not HOD mice had a detectable expansion of OVA-tetramer reactive CD4+ T cells, indicating that peripheral tolerance was preventing HOD autoreactive CD4+ T cells from participating in an immune response. To assess B cell tolerance to the HOD antigen, T cell tolerance was circumvented through adoptive transfer or OTII splenocytes (specific for the OVA323-339 peptide) into HOD mice. Anti-HEL autoantibodies were detected in HOD mice but not control B6 mice (p<0.001). Antibody production correlated with a 10–20 fold increase of anti-HEL antibody secreting cells, as determined by ELISPOT. Autoantibody production in HOD mice was not due to passenger B cells from the OTII donor, an artifact of excess CD4+ T cell number, or bystander activation as no autoantibodies were observed upon adoptive transfer with OTIIs on a Rag knockout background, irrelevant CD4+ T cells from SMARTA mice, or activated CD4+ T cells from TCR75 mice. To test the effects of HOD antigen expression on development of autoreactive B cells, HOD mice were crossed with SwHEL BCR transgenic mice (that express anti-HEL) and the F1 mice were analyzed. HEL-reactive B cells were visualized using multimeric HEL conjugated to allophycocyanin. In HOD-SwHEL+ mice, approximately 46±14% of immature bone marrow B cells were reactive with HEL, compared to 15±12% in HOD+SwHEL+ mice (p=0.043, 3 independent experiments, 5 mice total). Conclusions: These data demonstrate that tolerance to an RBC specific antigen is complete in the CD4+ T cell, but not the B cell compartment. CD4+ T cell tolerance appears to be more an effect of peripheral tolerance than central deletion, as OVA-tetramer reactive CD4+ T cells were visible in HOD mice but did not activate upon immunization with their cognate antigen. In contrast, while the HODxSwHEL F1 mice demonstrate that some B cell tolerance to HOD occurs, the induction of autoantibodies by introducing CD4+ autoreactive T cells (OT-II) demonstrates that B cell tolerance to the HOD antigen is incomplete in HOD mice. Together, these data suggest that a breakdown in T cell tolerance is all that is required for the pathogenesis of AIHA. As the T cell tolerance appears not to be deletional, it is predicted that environmental factors leading to a breakdown in peripheral tolerance of CD4+ T cells would be sufficient to induce AIHA. Disclosures: Zimring: Immucor Inc,: Research Funding.

scholarly journals Repression of B7.2 on Self-reactive B Cells Is Essential to Prevent Proliferation and Allow Fas-mediated Deletion by CD4+ T Cells

1998 ◽  
Vol 188 (4) ◽  
pp. 651-659 ◽  
Author(s):  
Jeffrey C. Rathmell ◽  
Sylvie Fournier ◽  
Bennett C. Weintraub ◽  
James P. Allison ◽  
Christopher C. Goodnow
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Fas Ligand ◽  
Costimulatory Molecule ◽  
Clonal Expansion ◽  
Early Response ◽  
Peripheral Tolerance

Peripheral tolerance mechanisms normally prevent delivery of T cell help to anergic self-reactive B cells that accumulate in the T zones of spleen and lymph nodes. Chronic exposure to self-antigens desensitizes B cell antigen receptor (BCR) signaling on anergic B cells so that they are not stimulated into clonal expansion by CD4+ T cells but instead are eliminated by Fas (CD95)-induced apoptosis. Because a range of BCR-induced signals and responses are repressed in anergic B cells, it is not known which of these are critical to regulate for Fas-mediated peripheral tolerance. Display of the costimulatory molecule, B7.2 (CD86), represents a potentially important early response to acute BCR engagement that is poorly induced by antigen on anergic B cells. We show here that restoring B7.2 expression on tolerant B cells using a constitutively expressed B7.2 transgene is sufficient to prevent Fas-mediated deletion and to trigger extensive T cell–dependent clonal expansion and autoantibody secretion in the presence of specific T cells. Dysregulated expression of B7.2 on tolerant B cells caused a more extreme reversal of peripheral tolerance than that caused by defects in Fas or Fas ligand, and resulted in T cell–dependent clonal expansion and antibody secretion comparable in magnitude to that made by foreign antigen-specific B cells. These findings demonstrate that repression of B7.2 is critical to eliminate autoreactive B cells by Fas in B cell–T cell interactions. The possible role of B7.2 dysregulation in systemic autoimmune diseases is discussed.

scholarly journals Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release.

1984 ◽  
Vol 160 (6) ◽  
pp. 1717-1735 ◽  
Author(s):  
K Inaba ◽  
R M Steinman
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Lymphocytes ◽  
B Cell ◽  
Interleukin 2 ◽  
Specific Antigen ◽  
Histocompatibility Complex ◽  
Ia Antigens ◽  
Antigen Presenting

Previous studies have shown that unprimed or resting T lymphocytes will grow and release lymphokines when stimulated by dendritic cells (DC). We now have examined the stimulatory requirements for antigen-primed or blast-transformed T cells. The latter were derived from dendritic/T cell clusters that developed during the primary mixed leukocyte reaction (MLR). The specificity of the blasts was established by a binding assay in which most T cells aggregated small B lymphocytes of the appropriate haplotype within 2 h at 4 or 37 degrees C. Since unprimed T cells did not aggregate allogeneic B cells, we suggest that DC induce T lymphocytes to express additional functioning receptors for antigen. Lyt-2-T blasts did not grow or release interleukin 2 or B cell helper factors unless rechallenged with specific alloantigen, whereupon growth (generation time of 14-18 h) and lymphokine release rapidly resumed. The blasts could be stimulated by allogeneic macrophages, B cells, and B lymphoblasts, whereas the primary MLR was initiated primarily by DC. responsiveness appeared restricted to the I region of the major histocompatibility complex, and varied directly with the level of Ia antigens on the stimulator cells. The interaction of B cells and T blasts was bidirectional. The T blasts would grow and form B cell helper factors, while the B cells grew and secreted antibody. However, the efficacy of T cell-mediated antibody formation was enhanced some 10-fold by the addition of specific antigen. Therefore, responses of resting helper T cells, then, are initiated by antigen plus DC. Once sensitized, T blasts interact independently with antigen presented by other leukocytes.

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