scholarly journals Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen.

1992 ◽  
Vol 176 (4) ◽  
pp. 991-1005 ◽  
Author(s):  
R Brink ◽  
C C Goodnow ◽  
J Crosbie ◽  
E Adams ◽  
J Eris ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
B Lymphocyte ◽  
Specific Antigen ◽  
Antigen Receptors ◽  
Antigen B ◽  
Self Antigen ◽  
Clonal Anergy

A series of immunoglobulin (Ig)-transgenic mice were generated to study the functional capabilities of the IgM and IgD classes of B lymphocyte antigen receptor in regulating both cellular development and responses to specific antigen. B cells from Ig-transgenic mice expressing either hen-egg lysozyme (HEL)-specific IgM or IgD alone were compared with B cells from mice that coexpressed IgM and IgD of the same anti-HEL specificity. In all three types of Ig-transgenic mice, conventional B cells specific for HEL exhibited exclusion of endogenous Ig expression and matured to populate the usual microenvironments in peripheral lymphoid tissues. These peripheral B cells could be stimulated by HEL through either IgM or IgD antigen receptors to generate T cell dependent antibody production in vivo or to enhance T cell independent proliferative responses to lipopolysaccharide in vitro. Conversely, when HEL was encountered in vivo as a self-antigen, B cells expressing HEL-specific IgM or IgD alone were both rendered tolerant. In each case this occurred by clonal anergy in response to soluble autologous HEL, and clonal deletion when HEL was recognized as a membrane-bound self-antigen. Taken together, these findings indicate that IgM and IgD antigen receptors expressed alone on conventional B cells can support normal differentiation, antigen-dependent activation, and induction of self-tolerance, the only overt difference lying in a greater degree of receptor downregulation for IgM relative to IgD after induction of clonal anergy by soluble HEL.

scholarly journals B cells solicit their own help from T cells.

1996 ◽  
Vol 183 (3) ◽  
pp. 891-899 ◽  
Author(s):  
B Stockinger ◽  
T Zal ◽  
A Zal ◽  
D Gray
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
Cell Receptor ◽  
Type Contact ◽  
Antigen Presenting ◽  
Self Antigen

We have made use of T cell receptor (TCR)-transgenic mice with CD4+ T cells expressing a receptor specific for the self-antigen C5 (fifth component of complement) to study the role of different antigen-presenting cells in the determination of CD4+ T cell effector type. Contact of T cells from C5 TCR-transgenic mice with C5 protein or C5 peptide in vivo or in vitro induces biased T helper cell (Th) 1 type responses resulting in exclusive production of high levels of interferon gamma and interleukin (IL) 2. Transgenic mice, in contrast to nontransgenic littermates, do not generate an antibody response to C5. We show in this paper that B cell presentation in vitro induces a switch to the Th2 subset indicated by production of IL-4, and targetting C5 to B cells in vivo results in the generation of C5-specific antibodies.

scholarly journals Loss of the Pro-Apoptotic BH3-only Bcl-2 Family Member Bim Inhibits BCR Stimulation–induced Apoptosis and Deletion of Autoreactive B Cells

2003 ◽  
Vol 198 (7) ◽  
pp. 1119-1126 ◽  
Author(s):  
Anselm Enders ◽  
Philippe Bouillet ◽  
Hamsa Puthalakath ◽  
Yuekang Xu ◽  
David M. Tarlinton ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Family Member ◽  
B Lymphocyte ◽  
Survival Function ◽  
Autoreactive B Cells ◽  
Induced Apoptosis ◽  
Self Antigen

During development, the stochastic process assembling the genes encoding antigen receptors invariably generates B and T lymphocytes that can recognize self-antigens. Several mechanisms have evolved to prevent the activation of these cells and the concomitant development of autoimmune disease. One such mechanism is the induction of apoptosis in developing or mature B cells by engagement of the B cell antigen receptor (BCR) in the absence of T cell help. Here we report that B lymphocytes lacking the pro-apoptotic Bcl-2 family member Bim are refractory to apoptosis induced by BCR ligation in vitro. The loss of Bim also inhibited deletion of autoreactive B cells in vivo in two transgenic systems of B cell tolerance. Bim loss prevented deletion of autoreactive B cells induced by soluble self-antigen and promoted accumulation of self-reactive B cells developing in the presence of membrane-bound self-antigen, although their numbers were considerably lower compared with antigen-free mice. Mechanistically, we determined that BCR ligation promoted interaction of Bim with Bcl-2, inhibiting its survival function. These findings demonstrate that Bim is a critical player in BCR-mediated apoptosis and in B lymphocyte deletion.

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.

scholarly journals Ig-specific T cell receptor-transgenic T cells are not deleted in the thymus and are functional in vivo.

1996 ◽  
Vol 183 (1) ◽  
pp. 203-213 ◽  
Author(s):  
F Granucci ◽  
M Rescigno ◽  
G Marconi ◽  
M Foti ◽  
P Ricciardi-Castagnoli
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cell Receptor Transgenic Mouse

The mechanisms that induce T cell tolerance to circulating self-proteins are still controversial, and both the deletion and selection of autoreactive T cells have been observed in the thymus of transgenic mouse models. To address the question of the induction of tolerance to circulating self-constituents, a T cell receptor-transgenic mouse specific for the serum protein immunoglobulin (Ig) gamma and (IgG2ab) was generated. The choice of an allotype-specific T cell also allowed the generation of transgenic control mice not expressing the self-antigen. It was found that the transgenic T cells were not deleted in the thymus, did not become tolerant in the periphery, and regulated the function of gamma 2ab-positive B cells as shown by the lack of IgG2ab protein in the serum of the transgenic mice. In spite of this activity in vivo, the transgenic T cells did not proliferate in vitro in response to the allotype-specific peptide. Interestingly, antigen-specific T cell proliferation could be restored if the transgenic mice were previously challenged to induce IgG2ab responses. After this challenge, IgG2ab protein in the serum of the transgenic mice could be partially restored, although still remaining much lower than in control mice. In addition, there was a dramatic increase in serum IgE levels, suggesting that newly generated gamma 2ab-secreting B cells can be induced to switch to IgE in the presence of allotype-specific T cells. These results indicate that Ig-specific T cells may represent a late-acting form of T cell help for the regulation of the IgG2a-to-IgE class switch.

scholarly journals Mice transgenic for a soluble form of murine CTLA-4 show enhanced expansion of antigen-specific CD4+ T cells and defective antibody production in vivo.

1994 ◽  
Vol 179 (3) ◽  
pp. 809-817 ◽  
Author(s):  
F Ronchese ◽  
B Hausmann ◽  
S Hubele ◽  
P Lane
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
T Cell Activation ◽  
Antibody Production ◽  
T Cell Responses ◽  
Soluble Form ◽  
Cell Responses

CD4+ T cell responses were analyzed in transgenic mice expressing a soluble form of murine CTLA-4, mCTLA4-H gamma 1, which blocks the interaction of the T cell activation molecules CD28 and CTLA-4 with their costimulatory ligands. Consistent with previous reports (Linsley, P. S., P. M. Wallace, J. Johnson, M. G. Gibson, J. L. Greene, J. A. Ledbetter, C. Singh, and M. A. Tepper. 1992. Science (Wash. DC). 257:792), T cell-dependent antibody production was profoundly inhibited in mCTLA4-H gamma 1 transgenic mice immunized with a protein antigen. Surprisingly, however, transgenic mice could generate quantitatively and qualitatively normal primary T cell responses, as measured by limiting dilution assays and lymphokine production. In addition, in vivo expansion of antigen-specific T cells after secondary or tertiary immunization was enhanced in mCTLA4-H gamma 1 transgenics as compared with normal mice. Although unable to deliver cognate help to B cells in vivo, T cells from mCTLA4-H gamma 1 transgenic mice were not anergic as they could help B cells to produce specific antibodies when adoptively transferred into nude hosts. Taken together, these data suggest that the engagement of CD28 and/or CTLA-4 may not be required for the induction of T cell responses, as is currently understood, but rather for the expression of T cell effector function such as the delivery of T cell help to B cells.

scholarly journals Selective B-cell expression of the MHV-68 latency-associated M2 protein regulates T-dependent antibody response and inhibits apoptosis upon viral infection

2013 ◽  
Vol 94 (7) ◽  
pp. 1613-1623 ◽  
Author(s):  
V. L. de Oliveira ◽  
S. C. P. Almeida ◽  
H. R. Soares ◽  
R. M. E. Parkhouse
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
B Lymphocyte ◽  
Inhibitory Influence ◽  
M2 Protein ◽  
Keyhole Limpet Haemocyanin ◽  
Cell Subpopulations

To better understand the role of the M2 protein of the murine herpes virus strain 68 (MHV-68) in vivo, B-lymphocyte-restricted, M2-transgenic mice were constructed. The transgenic mice contained normal B-cell subpopulations in bone marrow, lymph nodes and spleen. After immunization with sheep red blood cells, spleens from M2-transgenic mice had increased germinal centres. Transgenic mice responded to the T-cell-dependent antigen keyhole limpet haemocyanin (KLH) with higher levels of secondary IgM and IgG2a antibodies than WT mice. Normal and M2-transgenic mice were infected with WT and M2 frame-shift mutant (M2FS) MHV-68 viruses. The pathogenesis of M2-transgenic mice infected with the M2-deficient mutant virus did not revert to that observed upon infection of normal mice with WT virus. However, the higher reactivation levels late after M2-transgenic mice were infected with WT virus reflected the importance of M2 as a target for the immune response, and thus with an impact on the establishment of latency. Finally, there was markedly less apoptosis in B-cells from M2-transgenic mice infected with either WT or M2FS mutant than from similarly infected WT mice, consistent with the published inhibitory influence of M2 on apoptosis in vitro. Thus, M2 provides a strategy to increase the pool of germinal centre B-cells through inhibition of apoptosis in the infected cell.

Self-Reactivity in a Lymphopenic Mouse: A Model of Acute Graft-versus-Host Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1341-1341
Author(s):  
Birgit Knoechel ◽  
Jens G. Lohr ◽  
Estelle Kahn ◽  
Abul K. Abbas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Acute Gvhd ◽  
Rapid Development ◽  
Graft Versus Host ◽  
Inflammatory Infiltrates ◽  
Self Antigen

Abstract Transfer of naive antigen-specific T cells into self-antigen expressing transgenic mice leads to the development of hyporesponsiveness and deletion of the self-reactive T cells. This form of functional tolerance is characterized by decreased recall responses both in vivo and in vitro. Although the development of tolerance has been studied extensively, few studies have analyzed the factors that determine the breakdown of tolerance and how host cell populations influence the process. Using transgenic mice that express a secreted form of ovalbumin (sOVA Tg) in the serum either on a wildtype (WT) or a T-cell deficient (TCRa−/−), or B- and T-cell deficient (Rag−/−) background, we investigate tolerance development of OVA-specific DO11.10 CD4+ T cells that have been transferred into these mice. We report kinetics, phenotypes and cytokine production of the antigen-specific T cells after transfer. We further describe the histological, immunohistochemical and clinical picture and the effects of cytokine blockade by administration of antibodies. Naïve OVA-specific T cells that encounter OVA as a self-antigen in lymphocyte-sufficient recipients undergo some expansion, followed by a contraction phase, and become functionally hyporesponsive to the antigen. In contrast, adoptive transfer of DO11 cells into Rag-deficient sOVA Tg animals results in rapid development of wasting and death, phenotypically and histologically resembling cytokine release syndrome or acute GvHD. Histologic examination reveals inflammatory infiltrates predominantly in the skin and gut. Under these circumstances the transferred DO11 cells undergo massive expansion and produce abundant amounts of IL-2 and IFN-g. In contrast, transfer into TCRa-deficient sOVA Tg animals, in which B cells are present, leads to similar T cell expansion but substantially reduced IFN-g production and no death. Our data suggest that T cell tolerance in vivo is critically dependent on an intact, lymphocyte-sufficient host. In the absence of endogenous lymphocytes, T cells specific for a systemic self-antigen are activated and cause lethal immune reactions.

scholarly journals Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen.

1994 ◽  
Vol 180 (6) ◽  
pp. 2089-2099 ◽  
Author(s):  
T Zal ◽  
A Volkmann ◽  
B Stockinger
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Tolerance Induction ◽  
Cell Receptor ◽  
Double Positive ◽  
Single Positive ◽  
Self Antigen

Transgenic mice expressing a major histocompatibility complex class II-restricted T cell receptor with specificity for a natural self-antigen, the fifth component of complement, were generated to analyze the mechanism of tolerance induction to a blood-borne self-protein. In the absence of C5 protein thymocytes from T cell receptor transgenic mice develop into mature CD4 single positive cells which emigrate into the periphery and mount C5-specific T cell responses upon immunization with C5. In the presence of circulating C5 protein, CD4 single positive thymocytes do not develop. Negative selection occurs late in thymic ontogeny leaving the bulk of CD4+8+ thymocytes unaffected. This phenotype may be due to a delay in contact with self-antigen presentation which, under physiological conditions, is inefficient in the cortex of C5+ mice, and therefore does not affect most immature double positive thymocytes. In contrast, in vitro exposure to C5(-)-presenting dendritic cells or in vivo injection of C5 peptide results in deletion of double positive thymocytes. C5+ transgenic mice are tolerant in vivo, but contain T cells in spleen and lymph nodes that secrete interleukin 2 and interferon gamma in response to C5 activation in vitro. When crossed onto a Rag1-/- background to prevent endogenous T cell receptor rearrangements, these peripheral potentially autoreactive cells do not appear. This indicates that endogenous T cell receptor rearrangements possibly leading to the expression of two receptors might be a prerequisite for their survival and export into the periphery.

scholarly journals CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation.

1996 ◽  
Vol 183 (4) ◽  
pp. 1707-1718 ◽  
Author(s):  
K F Byth ◽  
L A Conroy ◽  
S Howlett ◽  
A J Smith ◽  
J May ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cross Linking ◽  
Thymocyte Development ◽  
Double Positive

The CD45 transmembrane glycoprotein has been shown to be a protein phosphotyrosine phosphatase and to be important in signal transduction in T and B lymphocytes. We have employed gene targeting to create a strain of transgenic mice that completely lacks expression of all isoforms of CD45. The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls. The increase in B cell numbers is due to the specific expansion of two B cell subpopulations that express high levels of immunoglobulin (IgM) staining. T cell development is significantly inhibited in CD45-null animals at two distinct stages. The efficiency of the development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by twofold, subsequently the frequency of successful maturation of the double positive population into mature, single positive thymocytes is reduced by a further four- to fivefold. In addition, we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be induced normally in CD45-null thymocytes by non-TCR-mediated signals. Since both positive and negative selection require signals through the TCR complex, these findings suggest that CD45 is an important regulator of signal transduction via the TCR complex at multiple stages of T cell development. CD45 is absolutely required for the transmission of mitogenic signals via IgM and IgD. By contrast, CD45-null B cells proliferate as well as wild-type cells to CD40-mediated signals. The proliferation of B cells in response to CD38 cross-linking is significantly reduced but not abolished by the CD45-null mutation. We conclude that CD45 is not required at any stage during the generation of mature peripheral B cells, however its loss reveals a previously unrecognized role for CD45 in the regulation of certain subpopulations of B cells.

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