Alterations in the Spinal Cord T Cell Repertoire During Relapsing Experimental Autoimmune Encephalomyelitis

Fritz, Robert B.; Wang, Xudong; Zhao, Ming-Lang

doi:10.4049/jimmunol.164.12.6662

Cited by 8 publications

(8 citation statements)

References 33 publications

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“…down-regulation of one or more dominant disease-causing clones may be inefficient, owing to either poor apoptotic depletion or insufficient bystander suppression, permitting newer recruits to cause new waves of disease. For example, in PLP-reactive T cell clone-induced EAE, the dominant encephalitogenic clone always remains at a predominant level in the CNS following relapses (36,37). It remains to be shown whether if this clone were efficiently eliminated, new relapses might not occur.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Control Autoimmunity In Vivo by Inducing Apoptotic Depletion of Activated Pathogenic Lymphocytes

Madakamutil

Maricic

Sercarz

et al. 2003

The Journal of Immunology

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Clinical autoimmunity requires both activation of self-reactive T cells as well as a failure of peripheral tolerance mechanisms. We previously identified one such mechanism that involves regulatory T cells recognizing TCR Vβ8.2 chain-derived peptides in the context of MHC. How this regulation affects the fate of target Vβ8.2+ T lymphocytes in vivo that mediate experimental autoimmune encephalomyelitis has remained unknown. The present study using immunoscope and CFSE-labeling analysis demonstrates that the expansion of regulatory CD4 and CD8 T cells in vivo results in apoptotic depletion of the dominant, myelin basic protein-reactive Vβ8.2+ T cells, but not subdominant Vβ13+ T cells. The elimination of only activated T cells by this negative feedback mechanism preserves the remainder of the naive Vβ8.2+ T cell repertoire and at the same time results in protection from disease. These studies are the first in clearly elucidating the fate of myelin basic protein-specific encephalitogenic T cells in vivo following regulation.

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Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Control Autoimmunity In Vivo by Inducing Apoptotic Depletion of Activated Pathogenic Lymphocytes

Madakamutil

Maricic

Sercarz

et al. 2003

The Journal of Immunology

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“…Presumably, the activation of Ag-specific CD8 ϩ T cells by B7.2-expressing microglia generates an inflammatory environment into which bystander T cells are nonspecifically recruited. Several studies have shown that bystander T cells can indeed be nonspecifically recruited to the CNS but that their accumulation within the CNS is dependent on local Ag-specific interactions (52)(53)(54)(55). Despite the increased heterogeneity of the overall CNS CD8 ϩ T cell repertoire in mice with overt disease, some V␤ families nevertheless exhibited skewed CDR3 size distribution.…”

Section: Discussionmentioning

confidence: 99%

A Pathogenic Role for CD8+ T Cells in a Spontaneous Model of Demyelinating Disease

Brisebois

Zehntner

Estrada

et al. 2006

The Journal of Immunology

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Transgenic (Tg) mice that overexpress the costimulatory ligand B7.2/CD86 on microglia spontaneously develop a T cell-mediated demyelinating disease. Characterization of the inflammatory infiltrates in the nervous tissue revealed a predominance of CD8+ T cells, suggesting a prominent role of this T cell subset in the pathology. In this study, we show that the same neurological disease occurred in Tg mice deficient in the generation of CD4+ T cells, with an earlier time of onset. Analysis of the CD8+ T cell repertoire at early stage of disease revealed the presence of selected clonal expansions in the CNS but not in peripheral lymphoid organs. We further show that Tg animals deficient in IFN-γ receptor expression were completely resistant to disease development. Microglia activation that is an early event in disease development is IFN-γ dependent and thus appears as a key element in disease pathogenesis. Collectively, our data indicate that the spontaneous demyelinating disease in this animal model occurs as a consequence of an inflammatory response initiated through the activation of CNS-specific CD8+ T cells by Tg expression of B7.2 within the target organ. Thus, autoreactive CD8+ T cells can contribute directly to the pathogenesis of neuroinflammatory diseases such as multiple sclerosis.

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“…A preferential usage of variable (V) β chains has been reported in some forms of EAE and in MS (Burns et al 1989; Fritz et al 2000; Matsumoto et al 2003; Matsumoto 2005). Similarly, clonal expansion of T cells with certain CDR3 motifs has also been shown in EAE and MS (Matsumoto et al 2003; Matsumoto 2005).…”

Section: Role Of Immune Responsesmentioning

confidence: 96%

Neuropathogenesis of Theiler’s Murine Encephalomyelitis Virus Infection, An Animal Model for Multiple Sclerosis

Tsunoda

Fujinami

2009

J Neuroimmune Pharmacol

105

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Theiler's murine encephalomyelitis virus (TMEV) infection of mice is an experimental model for multiple sclerosis (MS). TMEV induces a biphasic disease in susceptible mouse strains. During the acute phase, 1 week after infection, TMEV causes polioencephalomyelitis characterized by infection and apoptosis of neurons in the gray matter of the brain. During the chronic phase, about 1 month after infection, virus infects glial cells and macrophages, and induces inflammatory demyelination with oligodendrocyte apoptosis and axonal degeneration in the white matter of the spinal cord. Although antibody, CD4 + , and CD8 + T cell responses against TMEV capsid proteins play important roles in neuropathogenesis, infectious virus with persistence is necessary to induce demyelination; in general, adoptive transfer of antibody or T cells alone did not induce central nervous system (CNS) disease. The TMEV model can be useful for testing new therapeutic strategies specifically as a viral model for MS. Therapies targeting adhesion molecules, axonal degeneration, and immunosuppression can be beneficial for pure autoimmune CNS demyelinating diseases, such as experimental autoimmune encephalomyelitis, but could be detrimental in virusinduced demyelinating diseases, such as progressive multifocal leukoencephalopathy.

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Alterations in the Spinal Cord T Cell Repertoire During Relapsing Experimental Autoimmune Encephalomyelitis

Cited by 8 publications

References 33 publications

Regulatory T Cells Control Autoimmunity In Vivo by Inducing Apoptotic Depletion of Activated Pathogenic Lymphocytes

Regulatory T Cells Control Autoimmunity In Vivo by Inducing Apoptotic Depletion of Activated Pathogenic Lymphocytes

A Pathogenic Role for CD8+ T Cells in a Spontaneous Model of Demyelinating Disease

Neuropathogenesis of Theiler’s Murine Encephalomyelitis Virus Infection, An Animal Model for Multiple Sclerosis

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