An acetylcholine receptor alpha subunit promoter confers intrathymic expression in transgenic mice. Implications for tolerance of a transgenic self-antigen and for autoreactivity in myasthenia gravis.

Salmon, Anne-Marie; Bruand, Corinne; Cardona, Ana; Changeux, J P; Berrih‐Aknin, Sonia

doi:10.1172/jci1615

Cited by 47 publications

(26 citation statements)

References 54 publications

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“…The discrepancy between ␤-gal-Tg and AchR-Tg mice as compared with SM-OVA mice suggests that CD4 ϩ T cell anergy in the first two models is due to thymic rather than muscle autoantigen expression. Regarding B cell tolerance, a specific Ab response was observed in ␤-gal-Tg1, AchR-Tg, and SM-OVA mice after autoantigen immunization in the presence of CFA, whereas ␤-gal-Tg2 mice did not respond (50,51). This indicates that, despite muscle and eventually thymic expression, it remains possible to induce a specific B cell response except when the autoantigen is expressed at very high levels in muscle such as the case in ␤-gal-Tg2 mice.…”

Section: Discussionmentioning

confidence: 97%

“…To study the pathogenesis of myasthenia gravis, Tg mice that express ␤-galactosidase (␤-gal) or a heterologous AchR under the control of chicken AchR ␣-chain promoter sequences have been developed (50,51). This resulted in muscle but also thymic expression of the transgene.…”

Section: Discussionmentioning

confidence: 99%

“…This resulted in muscle but also thymic expression of the transgene. Using different forms of the AchR promoter, two ␤-gal-Tg lines were obtained with low (␤-gal-Tg1) or high (␤-gal-Tg2) muscle and thymic expression (51). CD4 ϩ T cells of both ␤-gal-Tg and AchR-Tg mice appeared to be anergic because they could not respond in vitro to Ag restimulation after in vivo immunization.…”

Section: Discussionmentioning

confidence: 99%

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Functional Tolerance of CD8+ T Cells Induced by Muscle-Specific Antigen Expression

Calbo

Delagrèverie

Arnoult

et al. 2008

The Journal of Immunology

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Skeletal muscles account for more than 30% of the human body, yet mechanisms of immunological tolerance to this tissue remain mainly unexplored. To investigate the mechanisms of tolerance to muscle-specific proteins, we generated transgenic mice expressing the neo-autoantigen OVA exclusively in skeletal muscle (SM-OVA mice). SM-OVA mice were bred with OT-I or OT-II mice that possess a transgenic TCR specific for OVA peptides presented by MHC class I or class II, respectively. Tolerance to OVA did not involve clonal deletion, anergy or an increased regulatory T cell compartment. Rather, CD4+ T cell tolerance resulted from a mechanism of ignorance revealed by their response following OVA immunization. In marked contrast, CD8+ T cells exhibited a loss of OVA-specific cytotoxic activity associated with up-regulation of the immunoregulatory programmed death-1 molecule. Adoptive transfer experiments further showed that OVA expression in skeletal muscle was required to maintain this functional tolerance. These results establish a novel asymmetric model of immunological tolerance to muscle autoantigens involving Ag ignorance for CD4+ T cells, whereas muscle autoantigens recognized by CD8+ T cells results in blockade of their cytotoxic function. These observations may be helpful for understanding the breakage of tolerance in autoimmune muscle diseases.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Functional Tolerance of CD8+ T Cells Induced by Muscle-Specific Antigen Expression

Calbo

Delagrèverie

Arnoult

et al. 2008

The Journal of Immunology

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“…The level of this thymic expression of tissue-specific autoantigens may be crucial to immune tolerance, at least in the case of insulin: the second strongest genetic association with type 1 diabetes (after HLA) is with a polymorphism upstream of the insulin gene, whose type 1 diabetes-predisposing alleles are associated with substantially lower thymic insulin expression [10][11][12]. This concept is supported by mouse models, which demonstrate a strong relationship between a tissue representation by 'promiscuous' gene expression in the thymus and the development of tissue-specific autoimmune response [13][14][15][16][17][18]. Most work in the past few years on the regulation of this atypical expression process has been on the autoimmune regulator (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) (AIRE) transcription factor, which has a major role in the expression of most self-antigens in the thymus.…”

Section: Introductionmentioning

confidence: 99%

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Levi

Polychronakos

2009

Diabetologia

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Aims/hypothesis The expression of tissue-specific selfantigens in the thymus is essential for self-tolerance. Genetic susceptibility to type 1 diabetes correlates inversely with thymic insulin expression and, in mice, lowered levels of this expression result in T cell responses against insulin. This study was undertaken to examine whether thymic insulin expression is regulated by the same metabolic stimuli as in beta cells or by different inputs, possibly of an immune nature. Methods Ins2 mRNA changes in mouse thymus were evaluated in vivo, following intraperitoneal glucose injection. We also examined the effect of a high glucose concentration on Ins2 mRNA in clones of insulin-expressing medullary thymus epithelial cell lines (mTECs). The same in vitro system was used to evaluate the effect of IFN-γ and cell-tocell contact with thymocytes in co-culture. Results Ins2 mRNA was significantly increased in the pancreas following a glucose load, but remained unchanged in the thymus. Furthermore, stimulation of insulin-expressing mTECs in vitro with IFN-γ, a cytokine involved in T cell negative selection, decreased levels of insulin expression even though expression of Aire was increased. Last, coculture of mTECs with thymocytes resulted in an upregulation of both Aire and insulin expression. Conclusions/interpretation We conclude that regulation of insulin transcription in the thymus is not dependent on metabolic stimuli but it may, instead, be under the control of cytokines and cell-to-cell interactions with lymphoid cells. That this regulation is not always coordinated with that of Aire, a non-specific master switch, suggests insulinspecific mechanisms.

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“…In another model wherein ␤-galactosidase was expressed at high levels in the thymus, practically all Ag-specific T cells were deleted. However, by shortening the promoter, thymic expression levels were reduced resulting in the functional inactivation of only Th1 cells (27). Although these results correlate differential tolerance levels with thymic Ag expression levels, they are applicable in that the neo-self Ag is expressed at low levels within the thymus in our model (8), and we observed a similar induction of tolerance of only the high-avidity T cell subset.…”

Section: Nontransgenic Animalsmentioning

confidence: 47%

Discrete T Cell Populations with Specificity for a Neo-Self-Antigen Bear Distinct Imprints of Tolerance

Standifer¹,

Stacy²,

Kraig³

et al. 2007

The Journal of Immunology

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Mice expressing the Torpedo acetylcholine receptor α-chain as a neo-self-Ag exhibit a reduced frequency of T cells responding to the immunodominant epitope Tα146–162 indicating a degree of tolerance. We characterized tolerance induction in these animals by analyzing the residual Tα146–162-responsive T cell population and comparing it to that of nontransgenic littermates. Using CD4high sorting, we isolated the vast majority of Ag-reactive T cells from both strains of mice. Quantitative studies of the CD4high populations in transgenic mice following immunization with Tα146–162 revealed a diminished expansion of cells expressing the canonical TCRBV6 but not other TCRBV gene segments when compared with nontransgenic littermates. In addition, CD4high cells from transgenic mice were functionally hyporesponsive to Tα146–162 in terms of proliferation and cytokine secretion regardless of TCRBV gene segment use. TCR sequence analysis of transgenic Vβ6+CD4high cells revealed a reduced frequency of cells expressing a conserved motif within the TCRβ CDR3. Thus, the canonical Tα146–162 responsive, Vβ6+ population demonstrates both quantitative and qualitative deficits that correlate with an altered TCR repertoire whereas the non-Vβ6 population in transgenic mice exhibits only a reduction in peptide responsiveness, a qualitative defect. These data demonstrate that discrete autoreactive T cell populations with identical peptide/MHC specificity in Torpedo acetylcholine receptor-α-transgenic animals bear distinct tolerance imprints.

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An acetylcholine receptor alpha subunit promoter confers intrathymic expression in transgenic mice. Implications for tolerance of a transgenic self-antigen and for autoreactivity in myasthenia gravis.

Cited by 47 publications

References 54 publications

Functional Tolerance of CD8+ T Cells Induced by Muscle-Specific Antigen Expression

Functional Tolerance of CD8+ T Cells Induced by Muscle-Specific Antigen Expression

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Discrete T Cell Populations with Specificity for a Neo-Self-Antigen Bear Distinct Imprints of Tolerance

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