T-cell activation and receptor downmodulation precede deletion induced by mucosally administered antigen

Benson, Jacqueline; Campbell, Kim; Guan, Zhen; Gienapp, Ingrid E.; Stuckman, Scott; Forsthuber, Thomas G.; Whitacre, Caroline C.

doi:10.1172/jci10738

Cited by 79 publications

(74 citation statements)

References 33 publications

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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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…on days 0 and 2 postimmunization (p.i.). Clinical score was checked daily by two researchers blindly according to the 0 to 5 scale as follows 20 : 1, limp tail or waddling gait with tail tonicity; 2, waddling gait with limp tail (ataxia); 2.5, ataxia with partial limb paralysis; 3, full paralysis of one limb; 3.5, full paralysis of one limb with partial paralysis of second limb; 4, full paralysis of two limbs; 4.5, moribund; and 5, death. All work was performed in accordance with the guidelines for animal use and care at Thomas Jefferson University.…”

Section: Eae Induction and Nsc Treatmentmentioning

confidence: 99%

Evaluation of Bone Marrow- and Brain-Derived Neural Stem Cells in Therapy of Central Nervous System Autoimmunity

Yang

Yan

Ćirić

et al. 2010

The American Journal of Pathology

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease resulting from an autoimmune response against central nervous system (CNS) myelin. Inflammatory infiltration and demyelination of the CNS are hallmarks of MS and its animal model, experimental autoimmune encephalomyelitis (EAE).1-3 MS begins when peripherally activated myelin-reactive T cells infiltrate into the CNS, followed closely by other immune cells, including naïve myelin-reactive T cells, polyclonal T cells, macrophages, dendritic cells, B cells, and neutrophils.

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“…The IL-4-secreting cell number was determined as described previously (17). IL-10-secreting cell number was determined using an IL-10 Development ELISPOT Module and Blue Color ELISPOT Module (R&D Systems).…”

Section: Frequency Of Cytokine-producing Cells By Elispot Analysismentioning

confidence: 99%

Cutting Edge: Macrophage Migration Inhibitory Factor Is Necessary for Progression of Experimental Autoimmune Encephalomyelitis

Powell¹,

Papenfuss²,

McClain³

et al. 2005

The Journal of Immunology

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Macrophage migration inhibitory factor (MIF) has been implicated in the pathogenesis of inflammatory and autoimmune diseases. The role of MIF in the progression of experimental autoimmune encephalomyelitis (EAE) was explored using MIF−/− mice. Wild-type mice showed a progressive disease course, whereas MIF−/− mice exhibited acute signs but no further progression of clinical disease. MIF−/− mice displayed markedly elevated corticosterone levels and significant decreases in the inflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-6 before, during, and after EAE onset. Taken together, these findings support that MIF is an important mediator of EAE progression through glucocorticoid antagonism and up-regulation of the inflammatory response.

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T-cell activation and receptor downmodulation precede deletion induced by mucosally administered antigen

Cited by 79 publications

References 33 publications

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

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

Evaluation of Bone Marrow- and Brain-Derived Neural Stem Cells in Therapy of Central Nervous System Autoimmunity

Cutting Edge: Macrophage Migration Inhibitory Factor Is Necessary for Progression of Experimental Autoimmune Encephalomyelitis

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