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Guy Bordenave - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of mouse T Lymphocyte-induced suppression of the IgG2ab allotype and T Lymphocyte Tolerance to IgG2ab.
Archivum immunologiae et therapiae experimentalis, 2001Co-Authors: Laleh Majlessi, Guy BordenaveAbstract:In mice of the Igha immunoglobulin allotypic haplotype we found, the presence of T Lymphocytes with an inherent inhibitory activity against the expression of the IgG2a(b) allotype (IgG2a of the Ighb immunoglobulin allotypic haplotype). This constitutive anti-IgG2a(b) T Lymphocyte activity can be enhanced in vivo by what we called "sensitization", which usually consists of one or two intravenous injections of B splenocytes from Ighb congenic mice. When injected at birth, the resulting anti-IgG2a(b) T splenocytes induce, with 100% success, total, specific and chronic (but experimentally reversible) suppression of IgG2a(b) in Igh(a/b) F1 hybrid mice prepared by mating Igh congenic mice. Even if restricted to IgG2a(b) expression, this experimental model, which deals with an unambiguous case of T cell-mediated down-regulation of immunoglobulin production, provides a clear and powerful tool to dissect finely the behavior of the partners (T and B Lymphocytes) intervening in regulation within the immune system. For example, we observed that CD4 T Lymphocytes were necessary to obtain full recruitment of anti-IgG2a(b) CD8 T Lymphocytes during the sensitization, that suppression induction in anti-IgG2a(b) T splenocytes of newborn recipients required cooperation between CD4 and CD8 T Lymphocytes, and that CD8 T Lymphocytes were essential for suppression maintenance. We showed that this suppression was not characterized by an accumulation of B Lymphocytes containing the allotype they could not secrete or Cgamma2a(b) mRNA they could not translate. The recipient's immune system was not involved in the suppession maintenance; this was done by donor T Lymphocytes, which ensured the chronicity of IgG2a(b) suppression throughout the recipient's life. We demonstrated that the mechanism of this suppression implied an MHC-restricted presentation by target B Lymphocytes of Cy2a(b) peptides to the T cell receptor (TCR) of anti-IgG2a(b) T Lymphocytes. Notwithstanding the requirement of a CD4-CD8 T Lymphocyte cooperation during the induction phase, we functionally determined that the suppression induction implicated an MHC class I-, but not class II-restricted interaction. We also demonstrated the existence in vivo of alternative or concomitant use of perforine- and Fas-mediated cytotoxicity pathways in this T cell-induced IgG2a(b) suppression. Thus this suppression did not imply silencing IgG2a(b) production, but B Lymphocyte destruction by CD8 T Lymphocytes. Always using our suppression model, we demonstrated that an agonistic anti-CD40 treatment helps in recruiting CD8 cytotoxic T Lymphocytes, involved in immune regulatory functions and that CD40 expression on Ighb B Lymphocytes confronted with CD8 T Lymphocyte effectors only operating via the Fas pathway was involved in the total suppression of IgG2a(b) expression. The selection and maintenance of such normal T cell activity against the IgG2a(b) allotype in mice of different genetic backgrounds remain somewhat enigmatic. Indeed, we did not observe any similar activity against other immunoglobulin allotypes or isotypes. The intestinal flora had no influence on the emergence of this anti-IgG2a(b) T Lymphocyte activity, as it was untouched in germ-free-Igha mice when compared with normal Igha mice. More recently, this model offered an opportunity to study problems pertaining to immune Tolerance. For instance, we showed that the genetic elements involved in the building of anti-IgG2a(b) TCR were available in Igha and Ighb mice of different genetic backgrounds, but that somatic constraints, namely the perinatal presence of IgG2a(b), effectively prevented their acquisition, while its absence led to their spontaneous emergence. Consequently, we were able to induce anti-IgG2a(b) T Lymphocytes into a Tolerance state by injecting Igha mice with soluble IgG2a(b) during the perinatal period. However, the full T Lymphocyte Tolerance obtained in this manner was not definitively acquired, as it had reversed spontaneously when investigated 3 to 6 months after the end of tolerogen treatment, even when this treatment had been prolonged from the perinatal period to 9 months of age. The mechanisms (induction and reversion) of this Tolerance involves the physical elimination or the irreversible inactivation of the natural anti-IgG2a(b) T Lymphocyte clones and their resurgence, from bone-marrow precursors, as long as the thymus remains operational, but not the establishment of a reversible, functional unresponsiveness (anergy) or an active, cell-mediated inhibition of anti-IgG2a(b) T clones. We attempted to elucidate, in Ighb mice, whether the natural T Lymphocyte unresponsiveness to IgG2a(b) involved a central Tolerance mechanism and to identify the type of tolerogen implicated in this tolerogenesis. The experiments principally showed that this natural T Lymphocyte Tolerance to IgG2a(b) was mediated by a thymic mechanism; that the capacity to induce it was gradually acquired by Ighb thymuses and was most probably due to potentially IgG2a(b)-producing/presenting cells, progressively colonizing the developing thymus; and that a significantly decreased postnatal Cy2a(b) gene transcription correlated with the emergence of anti-IgG2a(b) T Lymphocytes in Igh(a/b) F1 (postnatally deprived of their B Lymphocyte compartment), which subjected them to autoimmune IgG2a(b)-allotype suppression.
Laleh Majlessi - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of mouse T Lymphocyte-induced suppression of the IgG2ab allotype and T Lymphocyte Tolerance to IgG2ab.
Archivum immunologiae et therapiae experimentalis, 2001Co-Authors: Laleh Majlessi, Guy BordenaveAbstract:In mice of the Igha immunoglobulin allotypic haplotype we found, the presence of T Lymphocytes with an inherent inhibitory activity against the expression of the IgG2a(b) allotype (IgG2a of the Ighb immunoglobulin allotypic haplotype). This constitutive anti-IgG2a(b) T Lymphocyte activity can be enhanced in vivo by what we called "sensitization", which usually consists of one or two intravenous injections of B splenocytes from Ighb congenic mice. When injected at birth, the resulting anti-IgG2a(b) T splenocytes induce, with 100% success, total, specific and chronic (but experimentally reversible) suppression of IgG2a(b) in Igh(a/b) F1 hybrid mice prepared by mating Igh congenic mice. Even if restricted to IgG2a(b) expression, this experimental model, which deals with an unambiguous case of T cell-mediated down-regulation of immunoglobulin production, provides a clear and powerful tool to dissect finely the behavior of the partners (T and B Lymphocytes) intervening in regulation within the immune system. For example, we observed that CD4 T Lymphocytes were necessary to obtain full recruitment of anti-IgG2a(b) CD8 T Lymphocytes during the sensitization, that suppression induction in anti-IgG2a(b) T splenocytes of newborn recipients required cooperation between CD4 and CD8 T Lymphocytes, and that CD8 T Lymphocytes were essential for suppression maintenance. We showed that this suppression was not characterized by an accumulation of B Lymphocytes containing the allotype they could not secrete or Cgamma2a(b) mRNA they could not translate. The recipient's immune system was not involved in the suppession maintenance; this was done by donor T Lymphocytes, which ensured the chronicity of IgG2a(b) suppression throughout the recipient's life. We demonstrated that the mechanism of this suppression implied an MHC-restricted presentation by target B Lymphocytes of Cy2a(b) peptides to the T cell receptor (TCR) of anti-IgG2a(b) T Lymphocytes. Notwithstanding the requirement of a CD4-CD8 T Lymphocyte cooperation during the induction phase, we functionally determined that the suppression induction implicated an MHC class I-, but not class II-restricted interaction. We also demonstrated the existence in vivo of alternative or concomitant use of perforine- and Fas-mediated cytotoxicity pathways in this T cell-induced IgG2a(b) suppression. Thus this suppression did not imply silencing IgG2a(b) production, but B Lymphocyte destruction by CD8 T Lymphocytes. Always using our suppression model, we demonstrated that an agonistic anti-CD40 treatment helps in recruiting CD8 cytotoxic T Lymphocytes, involved in immune regulatory functions and that CD40 expression on Ighb B Lymphocytes confronted with CD8 T Lymphocyte effectors only operating via the Fas pathway was involved in the total suppression of IgG2a(b) expression. The selection and maintenance of such normal T cell activity against the IgG2a(b) allotype in mice of different genetic backgrounds remain somewhat enigmatic. Indeed, we did not observe any similar activity against other immunoglobulin allotypes or isotypes. The intestinal flora had no influence on the emergence of this anti-IgG2a(b) T Lymphocyte activity, as it was untouched in germ-free-Igha mice when compared with normal Igha mice. More recently, this model offered an opportunity to study problems pertaining to immune Tolerance. For instance, we showed that the genetic elements involved in the building of anti-IgG2a(b) TCR were available in Igha and Ighb mice of different genetic backgrounds, but that somatic constraints, namely the perinatal presence of IgG2a(b), effectively prevented their acquisition, while its absence led to their spontaneous emergence. Consequently, we were able to induce anti-IgG2a(b) T Lymphocytes into a Tolerance state by injecting Igha mice with soluble IgG2a(b) during the perinatal period. However, the full T Lymphocyte Tolerance obtained in this manner was not definitively acquired, as it had reversed spontaneously when investigated 3 to 6 months after the end of tolerogen treatment, even when this treatment had been prolonged from the perinatal period to 9 months of age. The mechanisms (induction and reversion) of this Tolerance involves the physical elimination or the irreversible inactivation of the natural anti-IgG2a(b) T Lymphocyte clones and their resurgence, from bone-marrow precursors, as long as the thymus remains operational, but not the establishment of a reversible, functional unresponsiveness (anergy) or an active, cell-mediated inhibition of anti-IgG2a(b) T clones. We attempted to elucidate, in Ighb mice, whether the natural T Lymphocyte unresponsiveness to IgG2a(b) involved a central Tolerance mechanism and to identify the type of tolerogen implicated in this tolerogenesis. The experiments principally showed that this natural T Lymphocyte Tolerance to IgG2a(b) was mediated by a thymic mechanism; that the capacity to induce it was gradually acquired by Ighb thymuses and was most probably due to potentially IgG2a(b)-producing/presenting cells, progressively colonizing the developing thymus; and that a significantly decreased postnatal Cy2a(b) gene transcription correlated with the emergence of anti-IgG2a(b) T Lymphocytes in Igh(a/b) F1 (postnatally deprived of their B Lymphocyte compartment), which subjected them to autoimmune IgG2a(b)-allotype suppression.
Brigitta Stockinger - One of the best experts on this subject based on the ideXlab platform.
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t Lymphocyte Tolerance from thymic deletion to peripheral control mechanisms
Advances in Immunology, 1998Co-Authors: Brigitta StockingerAbstract:Publisher Summary This chapter discusses the central and peripheral Tolerance in the T-cell population and self-Tolerance in the B-cell population. The understanding of Tolerance induction in Lymphocyte subpopulations is exponentially advanced in the generation of T- and B-cell receptor transgenic mice. Initial contradictions that seem to appear as different transgenic models are published and have given way to overall consensus; at least as far as central Tolerance induction in the thymus is concerned. The first direct demonstration for the elimination of potentially autoreactive cells in the thymus came from studies of the T-cell repertoire to endogenous superantigens. T cells bearing Vβ segments that conferred binding to endogenous mouse mammary tumor viruses (Mtv) were absent from mice carrying these superantigens in their genome. One mechanism of deletion is terminal differentiation to short-lived effector cells that may die by apoptosis because of lymphokine depletion. The latter mechanism could be prominent for CD8 T cells. The activation of T cells requires at least two signals: a signal through the T-cell receptor and a second signal presumed to involve a co-stimulatory molecule(s) on an antigen-presenting cell.
Moncef Zouali - One of the best experts on this subject based on the ideXlab platform.
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subversion of b Lymphocyte Tolerance by hydralazine a potential mechanism for drug induced lupus
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Lynda Mazari, Meryem Ouarzane, Moncef ZoualiAbstract:Accumulating evidence indicates that epigenetic alterations contribute to exacerbated activation or deregulation of the mechanisms that maintain Tolerance to self-antigens in patients with lupus, a systemic autoimmune disease that can be triggered by medications taken to treat a variety of conditions. Here, we tested the effect of hydralazine, an antihypertensive drug that triggers lupus, on receptor editing, a chief mechanism of B Lymphocyte Tolerance to self-antigens. Using mice expressing transgenic human Igs, we found that hydralazine impairs up-regulation of RAG-2 gene expression and reduces secondary Ig gene rearrangements. Receptor editing was also partially abolished in a dose-dependent manner by a specific inhibitor of MEK1/2. Adoptive transfer of bone marrow B cells pretreated with hydralazine or with a MEK inhibitor to naive syngeneic mice resulted in autoantibody production. We conclude that, by disrupting receptor editing, hydralazine subverts B Lymphocyte Tolerance to self and contributes to generation of pathogenic autoreactivity. We also postulate that inhibition of the Erk signaling pathway contributes to the pathogenesis of hydralazine-induced lupus and idiopathic human lupus.
Susana Minguet - One of the best experts on this subject based on the ideXlab platform.
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caveolin 1 tetraspanin cd81 and flotillins in Lymphocyte cell membrane organization signaling and immunopathology
Biochemical Society Transactions, 2020Co-Authors: Annamaria Schaffer, Susana MinguetAbstract:The adaptive immune system relies on B and T Lymphocytes to ensure a specific and long-lasting protection of an individual from a wide range of potential pathogenic hits. Lymphocytes are highly potent and efficient in eliminating pathogens. However, Lymphocyte activation must be tightly regulated to prevent incorrect activity that could result in immunopathologies, such as autoimmune disorders or cancers. Comprehensive insight into the molecular events underlying Lymphocyte activation is of enormous importance to better understand the function of the immune system. It provides the basis to design therapeutics to regulate Lymphocyte activation in pathological scenarios. Most reported defects in immunopathologies affect the regulation of intracellular signaling pathways. This highlights the importance of these molecules, which control Lymphocyte activation and homeostasis impacting Lymphocyte Tolerance to self, cytokine production and responses to infections. Most evidence for these defects comes from studies of disease models in genetically engineered mice. There is an increasing number of studies focusing on Lymphocytes derived from patients which supports these findings. Many indirectly involved proteins are emerging as unexpected regulators of the immune system. In this mini-review, we focus in proteins that regulate plasma membrane (PM) compartmentalization and thereby impact the steady state and the activation of immunoreceptors, namely the T cell antigen receptor (TCR) and the B cell antigen receptor (BCR). Some of these membrane proteins are shown to be involved in immune abnormalities; others, however, are not thoroughly investigated in the context of immune pathogenesis. We aim to highlight them and stimulate future research avenues.
