Induction of Rapid T Cell Activation and Tolerance by Systemic Presentation of an Orally Administered Antigen

Gütgemann, Ines; Fahrer, Aude M.; Altman, John D.; Davis, Mark M.; Chien, Yueh‐hsiu

doi:10.1016/s1074-7613(00)80571-3

Cited by 205 publications

(147 citation statements)

References 43 publications

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“…6). The early induction and subsequent decrease in CD69 expression upon activation of Ag-specific T cells have been described by us and others and occur irrespective of the outcome of T cell activation (tolerance or immunity) (22,35,(45)(46)(47).…”

Section: Discussionmentioning

confidence: 83%

Induction of Rapid T Cell Activation, Division, and Recirculation by Intratracheal Injection of Dendritic Cells in a TCR Transgenic Model

Lambrecht

Pauwels

Groth

2000

The Journal of Immunology

167

173

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Dendritic cells (DCs) are thought to be responsible for sensitization to inhaled Ag and induction of adaptive immunity in the lung. The characteristics of T cell activation in the lung were studied after transfer of Ag-pulsed bone marrow-derived DCs into the airways of naive mice. Cell division of Ag-specific T cells in vivo was followed in a carboxyfluorescein diacetate succinimidyl ester-labeled cohort of naive moth cytochrome c-reactive TCR transgenic T cells. Our adoptive transfer system was such that transferred DCs were the only cells expressing the MHC molecule required for presentation of cytochrome c to transgenic T cells. Ag-specific T cell activation and proliferation occurred rapidly in the draining lymph nodes of the lung, but not in nondraining lymph nodes or spleen. No bystander activation of non-Ag-specific T cells was induced. Division of Ag-specific T cells was accompanied by transient expression of CD69, while up-regulation of CD44 increased with each cell division. Divided cells had recirculated to nondraining lymph nodes and spleen by day 4 of the response. In vitro restimulation with specific Ag revealed that T cells were primed to proliferate more strongly and to produce higher amounts of cytokines per cell. These data are consistent with the notion that DCs in the lung are extremely efficient in selecting Ag-reactive T cells from a diverse repertoire. The response is initially localized in the mediastinal lymph nodes, but subsequently spreads systemically. This system should allow us to study the early events leading to sensitization to inhaled Ag.

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Section: Discussionmentioning

confidence: 83%

Induction of Rapid T Cell Activation, Division, and Recirculation by Intratracheal Injection of Dendritic Cells in a TCR Transgenic Model

Lambrecht

Pauwels

Groth

2000

The Journal of Immunology

167

173

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“…33 Antigen taken up by the gastrointestinal tract has been shown to be presented by tolerogenic antigenpresenting cells within the liver 34 and spleen. 19 It remains to be shown whether in autochthonous liver tumors liver resident or tumor-associated antigen-presenting cells are responsible for T-cell tolerance induction. Furthermore, it would be interesting to investigate other mechanisms of intrahepatic T cell tolerance induction, such as Bim-dependent T cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Proliferation and expression of the early activation marker CD69 in antigen-specific OT I T cells was used as a surrogate marker for antigen recognition. 19 Interestingly, most transferred OT I T cells up-regulated CD69 both in the liver and in the spleen of c-myc/OVA tgϩ mice, in contrast to T cells transferred into c-myc/OVA tgϪ control mice at 24 hours after adoptive transfer (Fig. 3A, P Ͻ 0.001).…”

Section: Antigen-specific T Cells Migrate Into the Tumormentioning

confidence: 90%

Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation

et al. 2008

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The reason the adaptive immune system fails in advanced liver tumors is largely unclear. To address this question, we have developed a novel murine model that combines c-mycinduced autochthonous tumorigenesis with expression of a cognate antigen, ovalbumin (OVA). When c-myc/OVA transgenic mice were crossed with liver-specific inducer mice, multifocal hepatocellular carcinomas co-expressing OVA developed in a tetracycline-dependent manner with a short latency and 100% penetrance. Transferred OVA-specific T cells, although infiltrating the tumor at high numbers, were hyporesponsive, as evidenced by a lack of in vivo cytotoxicity and interferon gamma production. This allowed the tumor to progress even in the presence of large numbers of antigen-specific T cells and even after vaccination (OVA؉CpG-DNA). Interestingly, T cell receptor down-modulation was observed, which may explain antigen-specific hyporesponsiveness. This model is helpful in understanding liver cancer-specific mechanisms of T cell tolerance and dissection of antigen-specific and nonspecific mechanisms of immunotherapies in the preclinical phase. Clinical observations suggest that the immune system is important in keeping tumor growth under control. [3][4][5] However, the immune system is frequently unable to control tumor burden in patients suffering from advanced cancer arising in solid parenchymatous organs, such as the liver. One reason could be that the liver represents a tolerogenic environment for T cells. 6,7 Another reason could be that tolerance occurs because of a tolerizing microenvironment specific for advanced autochthonous tumors that arise spontaneously and slowly over time. Third, tumor antigen may be transported to lymphatic tissues for induction of cross-tolerance, which has been described as a mechanism of peripheral CD8 ϩ T cell tolerance induction against self-antigens. 8 Recent reports indicate that immune tolerance in spontaneous tumors occurs because of a failure of the adaptive immune system. 9,10 However, the mechanism of tolerance induction in autochthonous tumors remains poorly defined.Tumor antigen-specific immune responses are difficult to track, both in autochthonous tumor models and in patients, because antigens in spontaneous tumors are largely unknown or not sufficiently immunogenic. To circumvent this limitation, we generated a novel "patientlike" model of HCC, in which the adaptive T cell response can be studied. In particular, we aimed to characterize the adaptive T cell response in advanced au-

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“…The demonstration of molecular mimicry between these two proteins has broader implications with respect to MS that extends to the T cell repertoire. The consumption of milk and milk products provides a source of BTN-derived peptides that can cross the gut mucosa to stimulate Ag-specific immune responses both locally in gut-associated lymphoid tissue as well as in peripheral immune organs (51). This is a normal physiological event that induces oral tolerance, the systemic suppression of proinflammatory T cell responses to soluble dietary Ags (13).…”

Section: Discussionmentioning

confidence: 99%

Antibody Cross-Reactivity between Myelin Oligodendrocyte Glycoprotein and the Milk Protein Butyrophilin in Multiple Sclerosis

Guggenmos

Schubart

Ogg

et al. 2004

The Journal of Immunology

119

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The etiology of multiple sclerosis (MS) is believed to involve environmental factors, but their identity and mode of action are unknown. In this study, we demonstrate that Ab specific for the extracellular Ig-like domain of myelin oligodendrocyte glycoprotein (MOG) cross-reacts with a homologous N-terminal domain of the bovine milk protein butyrophilin (BTN). Analysis of paired samples of MS sera and cerebrospinal fluid (CSF) identified a BTN-specific Ab response in the CNS that differed in its epitope specificity from that in the periphery. This effect was statistically significant for the Ab response to BTN76–100 (p = 0.0026), which cosequestered in the CSF compartment with Ab to the homologous MOG peptide MOG76–100 in 34% of MS patients (n = 35). These observations suggested that intratheccal synthesis of Ab recognizing BTN peptide epitopes in the CNS was sustained by molecular mimicry with MOG. Formal evidence of molecular mimicry between the two proteins was obtained by analyzing MOG-specific autoantibodies immunopurified from MS sera. The MOG-specific Ab repertoire cross-reacts with multiple BTN peptide epitopes including a MOG/BTN76–100-specific component that occurred at a higher frequency in MS patients than in seropositive healthy controls, as well as responses to epitopes within MOG/BTN1–39 that occur at similar frequencies in both groups. The demonstration of molecular mimicry between MOG and BTN, along with sequestration of BTN-reactive Ab in CSF suggests that exposure to this common dietary Ag may influence the composition and function of the MOG-specific autoimmune repertoire during the course of MS.

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Induction of Rapid T Cell Activation and Tolerance by Systemic Presentation of an Orally Administered Antigen

Cited by 205 publications

References 43 publications

Induction of Rapid T Cell Activation, Division, and Recirculation by Intratracheal Injection of Dendritic Cells in a TCR Transgenic Model

Induction of Rapid T Cell Activation, Division, and Recirculation by Intratracheal Injection of Dendritic Cells in a TCR Transgenic Model

Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation

Antibody Cross-Reactivity between Myelin Oligodendrocyte Glycoprotein and the Milk Protein Butyrophilin in Multiple Sclerosis

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