scholarly journals Tolerance induction in B lymphocytes but thymus-dependent antigens. T cells may abrogate B-cell tolerance induction by prevent an antibody response.

1975 ◽  
Vol 141 (5) ◽  
pp. 974-989 ◽  
Author(s):  
J W Schrader
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Population ◽  
Priming Effect ◽  
Gamma Globulin ◽  
Tolerance Induction ◽  
Cell Tolerance ◽  
B Cell Tolerance

Thymus-dependent protein antigens such as fowl gamma globulin (FGG) and dinitrophenylated-human gamma globulin (DNP-HGG), readily induced tolerance of the B cell in the absence of T cells even when these antigens were not deaggregated. However, when the same doses of antigen were given in the presence of T cells, the B-cell population was shown to be protected from tolerance induction, especially when the antigen was not in a deaggregated form. In this case, there was in fact evidence of a priming effect, manifest in both the B-cell and T-cell populations. The priming effect on the B-cell population was demonstrated by an increased response of mice pretreated with DNP-HGG, upon challenge with DNP conjugated to a heterologous carrier. The priming effect on the T-cell population was evident in a helper effect demonstrated in vitro. However, when euthymic mice which had been pretreated with large doses of FGG or DNP-HGG were challenged with the homologous carrier, the results were different. In this case, there was a profound suppression of the response against the carrier or the hapten on that carrier. Suppressor activity was also demonstrated in vitro and was shown to be sensitive to treatment with anti-theta-serum plus complement. Additionally it was shown that the effector phase of the suppression had a definite nonantigen-specific component. Thus, in pretreated euthymic mice, provided the homologous carrier was present, the response to a heterologous carrier was also suppressed. To account for the observation that nondeaggregated antigens can induce B-cell tolerance in athymic mice, but B-cell priming and T-cell-mediated suppression in euthymic mice, it is proposed that B-cell tolerance occurs when antigen at some critical dose interacts with the B cell in the absence of some second signal. This second signal is normally provided by the macrophage, probably with the assistance of the T cell, and its effect is to divert the result of the interaction of the B cell with antigen towards immunization and away from tolerance induction. When a large dose of an antigen that tends to form aggregates is given to an animal possessing functional T cells, both T-dependent helper and T-dependent suppressor activities are generated, thus accounting for a situation where the B-cell population is immunized, but B-cell activation is suppressed in the presence of the original carrier.

scholarly journals The in vitro induction of immunological tolerance in the B lymphocyte by oligovalent thymus-dependent antigens.

1975 ◽  
Vol 141 (5) ◽  
pp. 962-973 ◽  
Author(s):  
J W Schrader
Keyword(s):  
T Cells ◽  
B Cell ◽  
Gamma Globulin ◽  
Tolerance Induction ◽  
Marginal Effect ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
In Vitro System

B-cell tolerance has been induced by oligovalent thymus-dependent antigens in an entirely in vitro system. Dissociated spleen cells from congenitally athymic (nu/nu) mice were preincubated for 24 h with 0.1 -- 1 mg/ml of either fowl gamma globulin (FGG) of DNP-human gamma globulin (DNP-HGG). After washing, the cells were tested for the ability to mount in vitro, thymus-independent responses against FGG and DNP. A state of specific responsiveness to either FGG or DNP was thus demonstrated. Features of this wholly in vitro system that paralleled previous findings on the in vivo induction of B-cell tolerance in nu/nu mice were the kinetics, 24 h being required for tolerance induction in either case, the abrogation of tolerance induction by the presence of POL both in vivo and in vitro, and finally the observation that in neither case was there a requirement for the antigens to be deaggregated. It was shown that DNP-(Fab) 2 fragments prepared from HGG induced DNP-specific tolerance indicating that the Fc piece was not required for tolerance induction in this in vitro system. DNP-bovine serum albumin was less effective than DNP-HGG or DNP-(Fab)2. Preincubation with subtoxic concentrations of DNP-lysine of DNP-epsilon-capric acid had only a marginal effect on DNP responsiveness. Since nu/nu mice, lacking in detectable T-cell function, were used as spleen cell donors, this work provides further evidence that B-cell tolerance to thymus-dependent antigens can be induced without the participation of T cells. It is suggested that B-cell tolerance to thymus-dependent antigens occurs when the antigen in a sufficient concentration and over a sufficient period of time has direct access to the B cell. This contact with antigen must be in the absence of an additional influence provided either by adjuvants like endotoxin or POL, or by activated macrophages, which may be stimulated by activated T cells; otherwise not tolerance but B-cell activation will occur.

scholarly journals B-cell tolerance. II. Trinitrophenyl human gamma globulin-induced tolerance in adult and neonatal murine B cells responsive to thymus- dependent and independent forms of the same hapten

1977 ◽  
Vol 145 (3) ◽  
pp. 778-783 ◽  
Author(s):  
JC Cambier ◽  
ES Vitetta ◽  
JW Uhr ◽  
Kettman JR
Keyword(s):  
B Cells ◽  
B Cell ◽  
Gamma Globulin ◽  
Tolerance Induction ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Adult Mice ◽  
Human Gamma Globulin ◽  
Induction Of Tolerance

Neonatal splenic B cells which are responsive to thymus-dependent antigens (TD) are exquisitely susceptible to induction of tolerance (1,2). This state of tolerance is not mediated by suppressor T cells and is not a result of suboptimal macrophage function (1 and footnote one). In adult mice, induction of B-cell tolerance is not achieved with doses of antigen 1,000-fold higher (1) than those required to produce the same degree of unresponsiveness in neonates. In contrast to these results, studies with T-independent (TI) antigens indicate that neonatal and adult splenic B cells are equally susceptible to tolerance induction (3,4). However, such studies have not ascertained whether the neonate is more resistant to tolerance induction or the adult is hypersusceptible, i.e., does the induction of tolerance in cells responsive to TI antigens resemble that of adult or neonatal cells responsive to TD antigens? The answer is pertinent to determining the relative maturity of the B cells which can be tolerized or respond to TI or TD antigens. We report here the direct comparison of tolerogen sensitivity of adult and neonatal TD and TI responses by inducing tolerance in vitro with trinitophenyl human gamma globulin (TNP(17)HgG) and assaying unresponsiveness with TD and TI forms of the TNP determinant.

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 BAFF and MyD88 signals promote a lupuslike disease independent of T cells

2007 ◽  
Vol 204 (8) ◽  
pp. 1959-1971 ◽  
Author(s):  
Joanna R. Groom ◽  
Carrie A. Fletcher ◽  
Stacey N. Walters ◽  
Shane T. Grey ◽  
Sally V. Watt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Autoimmune Disorder ◽  
Systemic Autoimmune Disease ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
T Cell Help

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies. However, the underlying cause of disease appears to relate to defects in T cell tolerance or T cell help to B cells. Transgenic (Tg) mice overexpressing the cytokine B cell–activating factor of the tumor necrosis factor family (BAFF) develop an autoimmune disorder similar to SLE and show impaired B cell tolerance and altered T cell differentiation. We generated BAFF Tg mice that were completely deficient in T cells, and, surprisingly, these mice developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did, however, require B cell–intrinsic signals through the Toll-like receptor (TLR)–associated signaling adaptor MyD88, which controlled the production of proinflammatory autoantibody isotypes. TLR7/9 activation strongly up-regulated expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which is a receptor for BAFF involved in B cell responses to T cell–independent antigens. Moreover, BAFF enhanced TLR7/9 expression on B cells and TLR-mediated production of autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, but requires TLR signaling and is independent of T cell help. It is possible that SLE patients with elevated levels of BAFF show a similar basis for disease.

scholarly journals Defective B cell tolerance in adult (NZB X MZW)F1 mice.

1980 ◽  
Vol 152 (3) ◽  
pp. 730-735 ◽  
Author(s):  
E A Goldings ◽  
P L Cohen ◽  
S F McFadden ◽  
M Ziff ◽  
E S Vitetta
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Gamma Globulin ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Epitope Density ◽  
Human Gamma Globulin ◽  
Specific Tolerance

Hapten-specific tolerance was induced in vitro by trinitrophenyl-human gamma globulin (TNP32HGG) to a comparable degree in B cells from adult autoimmune (NZB X NZW)F1 (B/W) mice and normal BDF1, CBA/J, and DBA/1J mice. When a lower epitope density tolerogen (TNP7HGG) was used, B/W mice were significantly less sensitive than normal mice to the induction of B cell tolerance. This finding of defective B cell tolerance in adult B/W mice is consistent with previous reports that document other B cell abnormalities that may relate to the expression of autoimmune disease.

scholarly journals Differential susceptibility of neonatal and adult murine spleen cells to in vitro induction of B-cell tolerance.

1976 ◽  
Vol 144 (1) ◽  
pp. 293-297 ◽  
Author(s):  
J C Cambier ◽  
J R Kettman ◽  
E S Vitetta ◽  
J W Uhr
Keyword(s):  
T Cells ◽  
B Cell ◽  
Differential Susceptibility ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Murine Splenocytes ◽  
Murine Spleen ◽  
Human Gamma Globulin

The relative susceptibility of neonatal and adult murine splenocytes to induction of B-cell tolerance was studied in vitro. Adult cells required approximately 1,000-fold more trinitrophenyl-human gamma globulin to be rendered tolerant than did cells from 9- to 12-day-old neonates. The potential effects of suppressor T cells were excluded by pretreating the cultured B cells with anti-Thy-1 and C' and the helper T cells with anti-Ly-2.2 and C'. The possible role of cell surface immunoglobulin isotypes in contributing to this observed difference is discussed.

scholarly journals CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

2002 ◽  
Vol 197 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Melanie S. Vacchio ◽  
Richard J. Hodes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
Cd8 Cells ◽  
Costimulatory Signal ◽  
Cd28 Costimulation

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

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