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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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IFN-γ production in a fraction of pathogenic T cells protects the cerebellum from inflammation. C57BL6/J mice received either 5 × 106 MOG35-55-specific Th1 cells generated in C57BL6/J (WT Th1; A and B), 5 × 106 MOG35-55-specific Th1 cells generated in IFN-γ–deficient (IFN-γ KO) mice (C and D), 5 × 106 WT and 5 × 106 IFN-γ KO (E and F), or 106 WT and 5 × 106 IFN-γ KO (G–J) as a single i.v. injection. 17 d after injection and after development of classical EAE (A, B, and E–H), nonclassical EAE (C and D), or both classical and nonclassical disease (I and J), spinal cord and cerebellum were collected and stained with H&E to reveal inflammation. Representative slides from five independent experiments are shown. Bars, 200 μm.
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fig3: IFN-γ production in a fraction of pathogenic T cells protects the cerebellum from inflammation. C57BL6/J mice received either 5 × 106 MOG35-55-specific Th1 cells generated in C57BL6/J (WT Th1; A and B), 5 × 106 MOG35-55-specific Th1 cells generated in IFN-γ–deficient (IFN-γ KO) mice (C and D), 5 × 106 WT and 5 × 106 IFN-γ KO (E and F), or 106 WT and 5 × 106 IFN-γ KO (G–J) as a single i.v. injection. 17 d after injection and after development of classical EAE (A, B, and E–H), nonclassical EAE (C and D), or both classical and nonclassical disease (I and J), spinal cord and cerebellum were collected and stained with H&E to reveal inflammation. Representative slides from five independent experiments are shown. Bars, 200 μm.

Mentions: As the clinical outcomes of classical and atypical disease appeared to be mutually exclusive, we wished to examine the relative dominance of the trafficking patterns associated with both WT Th1 cells and IFN-γ–deficient cells. To do so, we mixed MOG35-55-specific encephalitogenic cell lines from IFN-γ–deficient and WT mice at varying ratios and examined the mixed cell populations for their capacity to induce atypical and/or classical EAE clinical symptoms. Cotransfer of WT and IFN-γ–deficient MOG-specific Th1-polarized cells at a 1:1 ratio resulted in induction of classical EAE in the majority of mice treated (Table II). Histological examination revealed no difference in cell localization between mice with classical EAE that received either 1:1 mixed transfer populations or WT Th1 cells alone (Fig. 3). Cotransfer of WT non-CNS antigen-specific (anti-OVA) Th1-polarized cells and IFN-γ–deficient MOG-specific Th1-polarized cells at a 1:1 ratio resulted in atypical disease, demonstrating that antigen-specific signaling of transferred Th1 cells was required to determine the site of lesion localization (Table II). Thus, IFN-γ production in a large fraction of CNS antigen-specific transferred cells is sufficient to localize inflammatory infiltration to the spinal cord and prevent inflammation of the cerebellum.


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)

IFN-γ production in a fraction of pathogenic T cells protects the cerebellum from inflammation. C57BL6/J mice received either 5 × 106 MOG35-55-specific Th1 cells generated in C57BL6/J (WT Th1; A and B), 5 × 106 MOG35-55-specific Th1 cells generated in IFN-γ–deficient (IFN-γ KO) mice (C and D), 5 × 106 WT and 5 × 106 IFN-γ KO (E and F), or 106 WT and 5 × 106 IFN-γ KO (G–J) as a single i.v. injection. 17 d after injection and after development of classical EAE (A, B, and E–H), nonclassical EAE (C and D), or both classical and nonclassical disease (I and J), spinal cord and cerebellum were collected and stained with H&E to reveal inflammation. Representative slides from five independent experiments are shown. Bars, 200 μm.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: IFN-γ production in a fraction of pathogenic T cells protects the cerebellum from inflammation. C57BL6/J mice received either 5 × 106 MOG35-55-specific Th1 cells generated in C57BL6/J (WT Th1; A and B), 5 × 106 MOG35-55-specific Th1 cells generated in IFN-γ–deficient (IFN-γ KO) mice (C and D), 5 × 106 WT and 5 × 106 IFN-γ KO (E and F), or 106 WT and 5 × 106 IFN-γ KO (G–J) as a single i.v. injection. 17 d after injection and after development of classical EAE (A, B, and E–H), nonclassical EAE (C and D), or both classical and nonclassical disease (I and J), spinal cord and cerebellum were collected and stained with H&E to reveal inflammation. Representative slides from five independent experiments are shown. Bars, 200 μm.
Mentions: As the clinical outcomes of classical and atypical disease appeared to be mutually exclusive, we wished to examine the relative dominance of the trafficking patterns associated with both WT Th1 cells and IFN-γ–deficient cells. To do so, we mixed MOG35-55-specific encephalitogenic cell lines from IFN-γ–deficient and WT mice at varying ratios and examined the mixed cell populations for their capacity to induce atypical and/or classical EAE clinical symptoms. Cotransfer of WT and IFN-γ–deficient MOG-specific Th1-polarized cells at a 1:1 ratio resulted in induction of classical EAE in the majority of mice treated (Table II). Histological examination revealed no difference in cell localization between mice with classical EAE that received either 1:1 mixed transfer populations or WT Th1 cells alone (Fig. 3). Cotransfer of WT non-CNS antigen-specific (anti-OVA) Th1-polarized cells and IFN-γ–deficient MOG-specific Th1-polarized cells at a 1:1 ratio resulted in atypical disease, demonstrating that antigen-specific signaling of transferred Th1 cells was required to determine the site of lesion localization (Table II). Thus, IFN-γ production in a large fraction of CNS antigen-specific transferred cells is sufficient to localize inflammatory infiltration to the spinal cord and prevent inflammation of the cerebellum.

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