Multiple Sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) and CD8 T-cells are the predominant T-cell population in MS lesions. Given that transfer of CNS-specific CD8 T-cells results in an attenuated clinical demyelinating disease in C57BL/6 mice with immunization-induced experimental autoimmune encephalomyelitis (EAE), we investigated the cellular target(s) and mechanism(s) of autoreactive regulatory CD8 T-cells. We now report that myelin oligodendrocyte glycoprotein peptide (MOG35–55)-induced CD8 T-cells could also attenuate adoptively transferred, CD4 T-cell-mediated EAE. Whereas CD8−/− mice exhibited more severe EAE associated with increased autoreactivity and inflammatory cytokine production by myelin-specific CD4 T-cells, this was reversed by adoptive transfer of MOG-specific CD8 T-cells. These autoregulatory CD8 T-cells required in vivo MHC Class Ia (KbDb) presentation. Interestingly, MOG-specific CD8 T-cells could also suppress adoptively-induced disease using wildtype MOG35–55-specific CD4 T-cells transferred into KbDb−/− recipient mice, suggesting direct targeting of encephalitogenic CD4 T-cells. In vivo trafficking analysis revealed that autoregulatory CD8 T-cells are dependent on neuro-inflammation for CNS infiltration and their suppression/cytotoxicity of MOG-specific CD4 T-cells is observed both in the periphery and in the CNS. These studies provide important insights into the mechanism of disease suppression mediated by autoreactive CD8 T-cells in EAE.
Rhabdomyosarcoma (RMS) is a mesenchymal malignancy composed of neoplastic primitive precursor cells that exhibit histological features of myogenic differentiation. Despite intensive conventional multimodal therapy, patients with high-risk RMS typically suffer from aggressive disease. The lack of directed therapies against RMS emphasizes the need to further uncover the molecular underpinnings of the disease. In this Review, we discuss the notable advances in the model systems now available to probe for new RMS-targetable pathogenetic mechanisms, and the possibilities for enhanced RMS therapeutics and improved clinical outcomes.
Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model of multiple sclerosis, an immune-mediated demyelinating disorder of the central nervous system (CNS). We have previously shown that CNS-specific CD8+ T cells (CNS-CD8+) ameliorate EAE, at least in part through modulation of CNS-specific CD4+ T cell responses. In this study, we show that CNS-CD8+ also modulate the function of CD11c+ dendritic cells (DC), but not other APCs such as CD11b+ monocytes or B220+ B cells. DC from mice receiving either myelin oligodendrocyte glycoprotein-specific CD8+ (MOG-CD8+) or proteolipid protein-specific CD8+ (PLP-CD8+) T cells were rendered inefficient in priming T cell responses from naïve CD4+ T cells (OT-II) or supporting recall responses from CNS-specific CD4+ T cells. CNS-CD8+ did not alter DC subset distribution or MHC class II and CD86 expression, suggesting that DC maturation was not affected. However, the cytokine profile of DC from CNS-CD8+ recipients showed lower IL-12 and higher IL-10 production. These functions were not modulated in the absence of immunization with CD8-cognate antigen, suggesting an antigen-specific mechanism likely requiring CNS-CD8-DC interaction. Interestingly, blockade of IL-10 in vitro rescued CD4+ proliferation and in vivo expression of IL-10 was necessary for the suppression of EAE by MOG-CD8+. These studies demonstrate a complex interplay between CNS-specific CD8+ T cells, DC and pathogenic CD4+ T cells, with important implications for therapeutic interventions in this disease.
Objective:To determine the antigenic determinants and specific molecular requirements for the generation of autoregulatory neuroantigen-specific CD8+ T cells in models of multiple sclerosis (MS).Methods:We have previously shown that MOG35-55-specific CD8+ T cells suppress experimental autoimmune encephalomyelitis (EAE) in the C57BL/6 model. In this study, we utilized multiple models of EAE to assess the ability to generate autoregulatory CD8+ T cells.Results:We demonstrate that alternative myelin peptides (PLP178-191) and other susceptible mouse strains (SJL) generated myelin-specific CD8+ T cells, which were fully capable of suppressing disease. The disease-ameliorating function of these cells was dependent on the specific cognate myelin antigen. Generation of these autoregulatory CD8+ T cells was not affected by thymic selection, but was dependent on the presence of both CD4+ and CD8+ T-cell epitopes in the immunizing encephalitogenic antigen.Conclusions:These studies show that the generation of autoregulatory CD8+ T cells is a more generalized, antigen-specific phenomenon across multiple neuroantigens and mouse strains, with significant implications in understanding disease regulation.
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