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Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis.

Lees JR, Golumbek PT, Sim J, Dorsey D, Russell JH - J. Exp. Med. (2008)

Bottom Line: Transfer of WT Th1 cells into IFN-gamma receptor-deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-gamma-deficient T cells to WT hosts.Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-gamma-deficient systems.These data demonstrate that interaction between IFN-gamma and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

ABSTRACT
The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-gamma. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-gamma deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell-produced IFN-gamma during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN-gamma receptor-deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-gamma-deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-gamma-deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-gamma-deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN-gamma and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.

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T cell lines treated with IL-23 produce high levels of IL-17 MOG-specific T cell lines were generated in either C57BL/6 (WT) or IFN-γ–deficient (IFN-γ−/−) mice. T cell lines were produced in the presence either of IL-12 or IL-23+TGF-β+IL-6+IL-1 as described in Materials and methods. Cells were tested for cytokine production after activation with PMA and Ionomycin. Data shown were previously gated by forward and side scatter to include lymphocytes. The data shown are representative of lines developed in four separate experiments.
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fig2: T cell lines treated with IL-23 produce high levels of IL-17 MOG-specific T cell lines were generated in either C57BL/6 (WT) or IFN-γ–deficient (IFN-γ−/−) mice. T cell lines were produced in the presence either of IL-12 or IL-23+TGF-β+IL-6+IL-1 as described in Materials and methods. Cells were tested for cytokine production after activation with PMA and Ionomycin. Data shown were previously gated by forward and side scatter to include lymphocytes. The data shown are representative of lines developed in four separate experiments.

Mentions: It is clear that immunization with CFA produces a population of cells skewed toward the Th1 phenotype (Fig. 2, WT cells expanded in IL-2 alone). However, Th17 conditions (IL-23, IL-6, and TGF-β) increase the fraction of cells expressing IL-17, especially IFN-γ IL-17 double producers. As expected, MOG-specific T cell lines produced from IFN-γ–deficient mice contained greater numbers of IL-17–producing cells than Th1 lines produced from WT mice (Fig. 2). However, IFN-γ–deficient lines cultured under Th1 polarizing conditions contained numbers of IL-17–producing T cells far lower than the numbers of IL-17–producing cells present in WT cell lines developed under Th17 polarizing conditions (Fig. 2). An increase in IL-17–producing cells to levels greater than that associated with IFN-γ deficiency was not sufficient to induce changes in encephalitogenic cell localization equivalent to those associated with IFN-γ deficiency (Table I). Instead, WT T cells polarized to produce IL-17–induced clinical symptoms identical to those produced by WT cells cultured under Th1 polarizing conditions, albeit with delayed onset (Table I). Further, in vitro polarization played no role in determining the clinical outcome of transferred IFN-γ–deficient cell lines, with equivalent atypical clinical manifestations observed in both IFN-γ–deficient cell lines regardless of previous conditioning (Table I).


Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis.

Lees JR, Golumbek PT, Sim J, Dorsey D, Russell JH - J. Exp. Med. (2008)

T cell lines treated with IL-23 produce high levels of IL-17 MOG-specific T cell lines were generated in either C57BL/6 (WT) or IFN-γ–deficient (IFN-γ−/−) mice. T cell lines were produced in the presence either of IL-12 or IL-23+TGF-β+IL-6+IL-1 as described in Materials and methods. Cells were tested for cytokine production after activation with PMA and Ionomycin. Data shown were previously gated by forward and side scatter to include lymphocytes. The data shown are representative of lines developed in four separate experiments.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571937&req=5

fig2: T cell lines treated with IL-23 produce high levels of IL-17 MOG-specific T cell lines were generated in either C57BL/6 (WT) or IFN-γ–deficient (IFN-γ−/−) mice. T cell lines were produced in the presence either of IL-12 or IL-23+TGF-β+IL-6+IL-1 as described in Materials and methods. Cells were tested for cytokine production after activation with PMA and Ionomycin. Data shown were previously gated by forward and side scatter to include lymphocytes. The data shown are representative of lines developed in four separate experiments.
Mentions: It is clear that immunization with CFA produces a population of cells skewed toward the Th1 phenotype (Fig. 2, WT cells expanded in IL-2 alone). However, Th17 conditions (IL-23, IL-6, and TGF-β) increase the fraction of cells expressing IL-17, especially IFN-γ IL-17 double producers. As expected, MOG-specific T cell lines produced from IFN-γ–deficient mice contained greater numbers of IL-17–producing cells than Th1 lines produced from WT mice (Fig. 2). However, IFN-γ–deficient lines cultured under Th1 polarizing conditions contained numbers of IL-17–producing T cells far lower than the numbers of IL-17–producing cells present in WT cell lines developed under Th17 polarizing conditions (Fig. 2). An increase in IL-17–producing cells to levels greater than that associated with IFN-γ deficiency was not sufficient to induce changes in encephalitogenic cell localization equivalent to those associated with IFN-γ deficiency (Table I). Instead, WT T cells polarized to produce IL-17–induced clinical symptoms identical to those produced by WT cells cultured under Th1 polarizing conditions, albeit with delayed onset (Table I). Further, in vitro polarization played no role in determining the clinical outcome of transferred IFN-γ–deficient cell lines, with equivalent atypical clinical manifestations observed in both IFN-γ–deficient cell lines regardless of previous conditioning (Table I).

Bottom Line: Transfer of WT Th1 cells into IFN-gamma receptor-deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-gamma-deficient T cells to WT hosts.Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-gamma-deficient systems.These data demonstrate that interaction between IFN-gamma and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

ABSTRACT
The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-gamma. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-gamma deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell-produced IFN-gamma during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN-gamma receptor-deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-gamma-deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-gamma-deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-gamma-deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN-gamma and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.

Show MeSH
Related in: MedlinePlus