Defective TCR expression in transgenic mice constructed using cDNA‐based α‐ and β‐chain genes under the control of heterologous regulatory elements

Barnden, Megan; Allison, Janette; Heath, William R.; Carbone, Federico

doi:10.1046/j.1440-1711.1998.00709.x

Cited by 1,339 publications

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References 23 publications

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“…1A), so we examined the stimulatory function of Aire -/-DC. Purified CD4 + T cells from TCR transgenic mice (OT II) recognizing the ovalbumin (OVA) peptide (aa 323-339) [36] were cocultured with T-depleted APC derived from either Aire -/-or Aire +/+ pooled spleen and lymph nodes. We observed modest, but consistent stronger T cell response with Aire -/-as compared to Aire +/+ APC (data not included).…”

Section: Resultsmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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Section: Resultsmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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“…11c.OVA and OT-II mice were bred and maintained at the Biologic Research Facility, PA Hospital, Brisbane, Australia. OT-II mice carrying a transgenic TCR specific for I-A b /OVA 323-339 [45] were crossed with CD45.1 congenic C57BL/6.SJL-Ptprc a mice to generate mice bearing CD45.1 1 OT-II cells. 11c.OVA mice express a membrane-bound OVA construct under the control of the CD11c promoter, which targets OVA expression to CD11c hi conventional DC [13].…”

Section: Animalsmentioning

confidence: 99%

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

et al. 2010

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CD4 1 T cells are important effectors of inflammation and tissue destruction in many diseases of immune dysregulation. As memory T cells develop early during the preclinical stages of autoimmune and inflammatory diseases, immunotherapeutic approaches to treatment of these diseases, once established, must include the means to terminate memory T-cell responses. Traditionally, it has been considered that, due to their terminally differentiated nature, memory T cells are resistant to tolerance induction, although emerging evidence indicates that some immunotherapeutic approaches can terminate memory T-cell responses. Here, we demonstrate that CD4 1 memory T-cell responses can be terminated when cognate antigen is transgenically expressed in steady-state DC. Transfer of in-vitrogenerated CD4 1 memory T cells establishes, in nontransgenic recipients, a stable and readily recalled memory response to cognate antigen. In contrast, upon transfer to mice expressing cognate antigen targeted to DC, memory CD4 1 T cells undergo a phase of limited proliferation followed by substantial deletion, and recall responses are effectively silenced. This finding is important in understanding how to effectively apply immunotherapy to ongoing T-cell-mediated autoimmune and inflammatory diseases.Key words: CD4 1 T cells . DC . Tolerance See accompanying Commentary by Kurts IntroductionNegative selection and peripheral tolerance mechanisms jointly serve to limit the development of autoaggressive self-reactive T-cell responses. However, in autoimmune-prone individuals these control mechanisms can fail and autoimmune disease ensues. As autoimmune diseases progress, intra-and intermolecular determinant spreading occurs [1] and populations of effector and memory T cells become established. Therefore, unlike strategies directed at preventing the development of autoimmune disease, where induction of tolerance in naïve T cells may be all that is required, therapies aimed at terminating ongoing autoimmune disease must be capable of inactivating established populations of memory or activated effector T cells.Although naïve T cells are highly dependent on the presence or absence of costimulatory signals to determine the outcome of activation, costimulation appears to play little role in controlling the responses of memory and effector T cells [2,3] and these cells are considered costimulation independent. Because of this, in contrast to naïve T cells which are readily deleted or inactivated in the absence of costimulation memory T cells are widely regarded as potentially resistant to tolerance induction. If this were indeed the case, then effector and memory T cells represent a significant hurdle to therapeutic strategies aimed at treating autoimmune diseases. However, we have recently shown that memory and effector CD8 1 T cells are susceptible to tolerance induction when cognate antigen is expressed in DC and other APC types [4]. 2016The relative roles of CD4 1 and CD8 1 T cells in disease progression differ depending on the autoimmune disease bu...

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“…C57BL/6 and BALB/c mice were purchased from Jackson Laboratories (Bar Harbor, Maine, USA) or Harlan Winkelmann (Borchen, Germany). OVA-specific CD8 + T cell-transgenic OT-I mice [28], OVA-specific CD4 + T cell-transgenic OT-II mice [29] and mice deficient for TLR9, IFNaR or IFNc have been described elsewhere [30] and were all on a C57BL/6 background.…”

Section: Micementioning

confidence: 99%

Systemic application of CpG‐rich DNA suppresses adaptive T cell immunity via induction of IDO

et al. 2005

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CpG-rich oligonucleotides (CpG-ODN) bind to Toll-like receptor 9 (TLR9) and are used as powerful adjuvants for vaccination. Here we report that CpG-ODN not only act as immune stimulatory agents but can also induce strong immune suppression depending on the anatomical location of application. In agreement with the adjuvant effect, subcutaneous application of antigen plus CpG-ODN resulted in antigen-specific T cell activation in local lymph nodes. In contrast, systemic application of CpG-ODN resulted in suppression of T cell expansion and CTL activity in the spleen. The suppressive effect was mediated by indoleamine 2,3-dioxygenase (IDO) as indicated by the observation that CpG-ODN induced IDO in the spleen and that T cell suppression could be abrogated by 1-methyl-tryptophan (1-MT), an inhibitor of IDO. No expression of IDO was observed in lymph nodes after injection of CpG-ODN, explaining why suppression was restricted to the spleen. Studies with a set of knockout mice demonstrated that the CpG-ODN-induced immune suppression is dependent on TLR9 stimulation and independent of type I and type II interferons. The present study shows that for the use of CpG-ODN as an adjuvant in vaccines, the route of application is crucial and needs to be considered. In addition, the results indicate that down-modulation of immune responses by CpG-ODN may be possible in certain pathological conditions. See accompanying commentary: http://dx

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Defective TCR expression in transgenic mice constructed using cDNA‐based α‐ and β‐chain genes under the control of heterologous regulatory elements

Cited by 1,339 publications

References 23 publications

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses

Systemic application of CpG‐rich DNA suppresses adaptive T cell immunity via induction of IDO

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Defective TCR expression in transgenic mice constructed using cDNA‐based α‐ and β‐chain genes under the control of heterologous regulatory elements

Cited by 1,339 publications

References 23 publications

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

Systemic application of CpG‐rich DNA suppresses adaptive T cell immunity via induction of IDO

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Steady‐state antigen‐expressing dendritic cells terminate CD4⁺ memory T‐cell responses