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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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Atypical inflammation in IFN-γR–deficient mice does not require increased Il-17 production in adoptively transferred cells. MOG35-55-specific T cell lines were generated in CD90.1+ C57BL/6 mice and retroorbitally injected into either C57BL/6 (WT) or IFN-γR–deficient (γR−/−) mice at 5 × 106 cells/mouse. After disease onset, T cells were recovered from either the cerebellum and brainstem or the spinal cord. T cells were restimulated with PMA and Ionomycin and tested for their capacity to produce IFN-γ and IL-17. Perivascular lesions and invasive parenchymal lesions are indicated with an arrow and the letters P and I, respectively. Data shown is representative of three separate experiments that used tissue pooled from two mice.
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fig6: Atypical inflammation in IFN-γR–deficient mice does not require increased Il-17 production in adoptively transferred cells. MOG35-55-specific T cell lines were generated in CD90.1+ C57BL/6 mice and retroorbitally injected into either C57BL/6 (WT) or IFN-γR–deficient (γR−/−) mice at 5 × 106 cells/mouse. After disease onset, T cells were recovered from either the cerebellum and brainstem or the spinal cord. T cells were restimulated with PMA and Ionomycin and tested for their capacity to produce IFN-γ and IL-17. Perivascular lesions and invasive parenchymal lesions are indicated with an arrow and the letters P and I, respectively. Data shown is representative of three separate experiments that used tissue pooled from two mice.

Mentions: A recent study suggested that changes in the ratio of IL-17 and IFN-γ–producing pathogenic T cells determined CNS lesion localization (17). To determine if changes in pathogenic T cell cytokine profiles coincided with development of atypical EAE in IFN-γR KO mice, we examined the cytokine profile of leukocytes recovered from the CNS of WT mice or IFN-γR–deficient mice that received WT pathogenic cells (Fig. 6). Interestingly, a high number of the recently described (18) host CD4−CD8− IL-17–producing T cells were found in the cerebellum of mice with atypical EAE, suggesting that these cells may play a role in the pathogenesis of atypical EAE (Fig. 6). However, examination of adoptively transferred WT cells revealed no change in IL-17 production capacity regardless of the host's IFN-γR expression level and clinical manifestation (Fig. 6). Thus, the changes in lesion localization associated with IFN-γR deficiency are not a result of changes within the pathogenic T cells but instead reflect the inability of the host to respond to IFN-γ produced by the invasive T cell.


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)

Atypical inflammation in IFN-γR–deficient mice does not require increased Il-17 production in adoptively transferred cells. MOG35-55-specific T cell lines were generated in CD90.1+ C57BL/6 mice and retroorbitally injected into either C57BL/6 (WT) or IFN-γR–deficient (γR−/−) mice at 5 × 106 cells/mouse. After disease onset, T cells were recovered from either the cerebellum and brainstem or the spinal cord. T cells were restimulated with PMA and Ionomycin and tested for their capacity to produce IFN-γ and IL-17. Perivascular lesions and invasive parenchymal lesions are indicated with an arrow and the letters P and I, respectively. Data shown is representative of three separate experiments that used tissue pooled from two mice.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Atypical inflammation in IFN-γR–deficient mice does not require increased Il-17 production in adoptively transferred cells. MOG35-55-specific T cell lines were generated in CD90.1+ C57BL/6 mice and retroorbitally injected into either C57BL/6 (WT) or IFN-γR–deficient (γR−/−) mice at 5 × 106 cells/mouse. After disease onset, T cells were recovered from either the cerebellum and brainstem or the spinal cord. T cells were restimulated with PMA and Ionomycin and tested for their capacity to produce IFN-γ and IL-17. Perivascular lesions and invasive parenchymal lesions are indicated with an arrow and the letters P and I, respectively. Data shown is representative of three separate experiments that used tissue pooled from two mice.
Mentions: A recent study suggested that changes in the ratio of IL-17 and IFN-γ–producing pathogenic T cells determined CNS lesion localization (17). To determine if changes in pathogenic T cell cytokine profiles coincided with development of atypical EAE in IFN-γR KO mice, we examined the cytokine profile of leukocytes recovered from the CNS of WT mice or IFN-γR–deficient mice that received WT pathogenic cells (Fig. 6). Interestingly, a high number of the recently described (18) host CD4−CD8− IL-17–producing T cells were found in the cerebellum of mice with atypical EAE, suggesting that these cells may play a role in the pathogenesis of atypical EAE (Fig. 6). However, examination of adoptively transferred WT cells revealed no change in IL-17 production capacity regardless of the host's IFN-γR expression level and clinical manifestation (Fig. 6). Thus, the changes in lesion localization associated with IFN-γR deficiency are not a result of changes within the pathogenic T cells but instead reflect the inability of the host to respond to IFN-γ produced by the invasive T cell.

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