Contribution of CD8 T lymphocytes to the immuno-pathogenesis of multiple sclerosis and its animal models

INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Hôpital Purpan, Toulouse, F-31300, France
Biochimica et Biophysica Acta (Impact Factor: 4.66). 02/2011; 1812(2):151-61. DOI: 10.1016/j.bbadis.2010.07.006
Source: PubMed


Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by multi-focal demyelination, axonal loss, and immune cell infiltration. Numerous immune mediators are detected within MS lesions, including CD4(+) and CD8(+) T lymphocytes suggesting that they participate in the related pathogenesis. Although CD4(+) T lymphocytes are traditionally considered the main actors in MS immunopathology, multiple lines of evidence suggest that CD8(+) T lymphocytes are also implicated in the pathogenesis. In this review, we outline the recent literature pertaining to the potential roles of CD8(+) T lymphocytes both in MS and its animal models. The CD8(+) T lymphocytes detected in MS lesions demonstrate characteristics of activated and clonally expanded cells supporting the notion that these cells actively contribute to the observed injury. Moreover, several experimental in vivo models mediated by CD8(+) T lymphocytes recapitulate important features of the human disease. Whether the CD8(+) T cells can induce or aggravate tissue destruction in the CNS needs to be fully explored. Strengthening our understanding of the pathogenic potential of CD8(+) T cells in MS should provide promising new avenues for the treatment of this disabling inflammatory disease.

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    • "The animal model that is considered to most closely model multiple sclerosis is termed experimental autoimmune encephalomyelitis (EAE)25262728. EAE is thought to, in some aspects, replicate MS in terms of the inflammation and ensuing CNS demyelination2930. This animal model is induced by delivering an antigenic myelin-derived peptide along with an adjuvant that together initiate an inflammatory response producing autoreactive lymphocytes that target the host's endogenous myelin31. "
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    ABSTRACT: Fingolimod (FTY720) is an oral therapy for relapsing remitting multiple sclerosis (MS) and targets sphingosine 1-phosphate receptors (S1PRs). FTY720 also rescues animals from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effects of FTY720 in EAE are primarily scored manually by examining weight loss and limb paralysis that begins around 10-12 days after immunisation. To our knowledge, pre-clinical effects of FTY720 on animal behaviour early in EAE have not been explored. Here, we developed an automated behaviour monitoring system to examine the early effects of FTY720 on subtle pre-symptomatic behaviour of mice induced with EAE. Our automated home-cage monitoring system (AHC-MS) enabled non-contact detection of movement and ultrasonic vocalisations (USVs) of mice induced with EAE, thus allowing detection of subtle changes in mouse behaviour before paralysis occurs. Mice receiving FTY720 emit longer USVs and display higher levels of motor activity than vehicle-treated EAE mice before clinical symptoms become apparent. Importantly, this study promotes the 3Rs ethics (replacement, reduction and refinement) in the EAE animal model and may also improve pre-screening of potentially novel MS therapies. In addition, this is the first report showing the early effects of FTY720 in EAE which underscores its protective effects.
    Scientific Reports 05/2014; 4:5051. DOI:10.1038/srep05051 · 5.58 Impact Factor
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    • "Multiple sclerosis (MS), a chronic autoimmune disorder characterized pathologically by central nervous system (CNS) inflammation, demyelination, and axonal damage, has been traditionally attributed to self-reactive CD4+ T lymphocytes that escape tolerance [1]. Growing evidence, however, indicates that autoreactive CD8+ T cells, like their CD4+ counterparts, contribute to the induction, progression, and pathogenesis of autoimmune neuroinflammation [2,3]. Myelin-specific CD8+ T cells were reported to both aggravate CD4+ T cell-mediated experimental autoimmune encephalomyelitis (EAE) [4], an animal model for MS, and to mediate autoimmune CNS disease on their own [5-7]. "
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    ABSTRACT: Accumulating evidence suggests a deleterious role for CD8+ T cells in multiple sclerosis (MS) pathogenesis. We have recently reported that hepatocyte growth factor (HGF), a potent neuroprotective factor, limits CD4+ T cell-mediated autoimmune neuroinflammation by promoting tolerogenic dendritic cells (DCs) and subsequently regulatory T cells. Whether HGF modulates cell-mediated immunity driven by MHC class I-restricted CD8+ T cells remains to be determined. Here we examined whether HGF regulates antigen-specific CD8+ T cell responses using an established model of murine cytotoxic T lymphocyte (CTL)-mediated killing. We found that HGF treatment of gp100-pulsed DCs reduced the activation of gp100-specific T cell receptor (Pmel-1) CD8+ T cells and subsequent MHC class I-restricted CTL-mediated cytolysis of gp100-pulsed target cells. The levels of perforin, granzyme B, IFN-gamma, and the degranulation marker CD107a as well as Fas ligand were decreased among CD8+ T cells, suggestive of a dual inhibitory effect of HGF on the perforin/granzyme B- and Fas-based lytic pathways in cell-mediated cytotoxicity. Treatment of CD8+ T cells with concanamycin A, a potent inhibitor of the perforin-mediated cytotoxic pathway, abrogated CTL cytotoxicity indicating that blockade of the perforin-dependent killing is a major mechanism by which HGF diminished cytolysis of gp100-pulsed target cells. Moreover, HGF suppressed the generation of effector memory CTLs. Our findings indicate that HGF treatment limits both the generation and activity of effector CTL from naive CD8+ T cells. Complementary to its impact on CD4+ T-cell CNS autoimmunity and myelin repair, our findings further suggest that HGF treatment could be exploited to control CD8+ T-cell-mediated, MHC I-restricted autoimmune dysfunctions such as MS.
    Journal of Neuroinflammation 12/2013; 10(1):154. DOI:10.1186/1742-2094-10-154 · 5.41 Impact Factor
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    • "In general, EAE is a T cell-mediated disease highlighted by the fact that it can be transferred to naïve animals using pathogenic CD4 + (Zamvil and Steinman, 1990) or CD8 + T cells (Huseby et al., 2001; Sun et al., 2001). While CD4 + T cells alone are sufficient to induce EAE even in the absence of CD8 + T cells, many studies also speak in favor of an important role of CD8 + T and B cells in EAE (Cabarrocas et al., 2003; Ford and Evavold, 2005; Mars et al., 2011; Saxena et al., 2008; Ziemssen and Ziemssen, 2005). Furthermore, application of new techniques such as intravital imaging by 2-photon microscopy has allowed insight into the different phases of EAE (Bartholomäus et al., 2009). "
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    ABSTRACT: Glucocorticoids (GCs) are the most commonly prescribed drugs for the treatment of acute disease bouts in multiple sclerosis (MS) patients. While T lymphocytes were shown to be essential targets of GC therapy, at least in animal models of MS, the mechanisms by which GCs modulate T cell function are less clear. Until now, apoptosis induction and repression of pro-inflammatory cytokines in T cells have been considered the most critical mechanisms in ameliorating disease symptoms. However, this notion is being challenged by increasing evidence that the control of T cell migration and chemotaxis by GCs might be even more important for the treatment of neuroinflammatory diseases. In this review we aim to provide an overview of how GCs impact the morphological alterations that T cells undergo during activation and migration as well as the influences that GCs have on the directed movement of T cells under the influence of chemokines. A deeper understanding of these processes should not only help to advance our understanding of how GCs exert their beneficial effects in MS therapy but may reveal future strategies to intervene in the pathogenesis of neuroinflammatory diseases.
    Molecular and Cellular Endocrinology 04/2013; 380(1-2). DOI:10.1016/j.mce.2013.04.001 · 4.41 Impact Factor
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