Contribution of Astrocyte-Derived IL-15 to CD8 T Cell Effector Functions in Multiple Sclerosis

Saikali, Philippe; Antel, Jack P.; Pittet, Camille L.; Newcombe, Jia; Arbour, Nathalie

doi:10.4049/jimmunol.1002188

Cited by 93 publications

(98 citation statements)

References 79 publications

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“…Recent findings suggest that astrocytes play an active role during demyelination and oligodendrocyte degeneration by controlling local inflammation in the CNS, which damages OLs and axons [33] . Astrocyte production of IL-15 leads to the activation of CD8 T-lymphocytes that contribute to the exacerbation of tissue damage during MS [34] . Recent studies also suggest that aberrant upregulation of astroglial ceramide potentiates OL injury [35,36] .…”

Section: Discussionmentioning

confidence: 99%

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

Wang

et al. 2013

Neurosci. Bull.

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Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

Wang

et al. 2013

Neurosci. Bull.

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“…In MS patients, both soluble and membrane-bound IL-15 levels are increased in the serum and cerebrospinal fluid (29)(30)(31). Recently, increased IL-15 expression was found on peripheral B cells and on astrocytes within brain lesions of MS patients, compared with control subjects (24,32). The cytotoxicity-enhancing effect of IL-15 has already been described for NK cells and CD8 + T cells (24,(32)(33)(34).…”

mentioning

confidence: 86%

“…Recently, increased IL-15 expression was found on peripheral B cells and on astrocytes within brain lesions of MS patients, compared with control subjects (24,32). The cytotoxicity-enhancing effect of IL-15 has already been described for NK cells and CD8 + T cells (24,(32)(33)(34). Specifically, it was shown that the signaling pathways of IL-15 and the activating NK cell receptor NKG2D are intertwined (35).…”

mentioning

confidence: 99%

IL-15 Amplifies the Pathogenic Properties of CD4+CD28− T Cells in Multiple Sclerosis

Broux

Mizee

Vanheusden

et al. 2015

The Journal of Immunology

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CD4+CD28− T cells arise through repeated antigenic stimulation and are present in diseased tissues of patients with various autoimmune disorders, including multiple sclerosis (MS). These cells are believed to have cytotoxic properties that contribute to the pathogenic damaging of the target organ. Endogenous cues that are increased in the diseased tissue may amplify the activity of CD4+CD28− T cells. In this study, we focused on IL-15, a cytotoxicity-promoting cytokine that is increased in the serum and cerebrospinal fluid of MS patients. Using immunohistochemistry, we demonstrate that IL-15 is mainly produced by astrocytes and infiltrating macrophages in inflammatory lesions of MS patients. Moreover, in vitro transmigration studies reveal that IL-15 selectively attracts CD4+CD28− T cells of MS patients, but not of healthy individuals. IL-15 further induces the expression of chemokine receptors and adhesion molecules on CD4+CD28− T cells, as investigated using flow cytometry, resulting in enhanced migration over a monolayer of human brain endothelial cells. Finally, flow cytometric analyses revealed that IL-15 increases the proliferation and production of GM-CSF, expression of cytotoxic molecules (NKG2D, perforin, and granzyme B), and degranulation capacity of CD4+CD28− T cells. Taken together, these findings indicate that increased peripheral and local levels of IL-15 amplify the pathogenic potential of CD4+CD28− T cells, thus contributing to tissue damage in MS brain lesions.

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“…In addition to T cell anergy, activation-induced cell death and the proapoptotic molecule Bim keep autoreactive CD8 + T cells in check (19)(20)(21). Extrinsic mechanisms also operate to repress self-reactive T cells; these include availability of cytokines, such as IL-7 and IL-15 (22,23), and the suppressive effect of regulatory T cells through their ability to secrete IL-10 and TGF-b (24). Although IFN-g was shown to promote CD8 + T cell apoptosis during viral infection (25), a role for IFN-g in the regulation of self-reactive CD8 + T cell effectors has not been described.…”

Section: Cd8 + T Cells Responding To Viral Infections Initiate Their mentioning

confidence: 99%

Breakdown in Repression of IFN-γ mRNA Leads to Accumulation of Self-Reactive Effector CD8+ T Cells

Chang

Lee

et al. 2012

The Journal of Immunology

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Tight regulation of virus-induced cytotoxic effector CD8+ T cells is essential to prevent immunopathology. Naturally occurring effector CD8+ T cells, with a KLRG1hi CD62Llo phenotype typical of short-lived effector CD8+ T cells (SLECs), can be found in increased numbers in autoimmune-prone mice, most notably in mice homozygous for the san allele of Roquin. These SLEC-like cells were able to trigger autoimmune diabetes in a susceptible background. When Roquin is mutated (Roquinsan), effector CD8+ T cells accumulate in a cell-autonomous manner, most prominently as SLEC-like effectors. Excessive IFN-γ promotes the accumulation of SLEC-like cells, increases their T-bet expression, and enhances their granzyme B production in vivo. We show that overexpression of IFN-γ was caused by failed posttranscriptional repression of Ifng mRNA. This study identifies a novel mechanism that prevents accumulation of self-reactive cytotoxic effectors, highlighting the importance of regulating Ifng mRNA stability to maintain CD8+ T cell homeostasis and prevent CD8-mediated autoimmunity.

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Contribution of Astrocyte-Derived IL-15 to CD8 T Cell Effector Functions in Multiple Sclerosis

Cited by 93 publications

References 79 publications

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

IL-15 Amplifies the Pathogenic Properties of CD4+CD28− T Cells in Multiple Sclerosis

Breakdown in Repression of IFN-γ mRNA Leads to Accumulation of Self-Reactive Effector CD8+ T Cells

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