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The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis.

Kawakami N, Lassmann S, Li Z, Odoardi F, Ritter T, Ziemssen T, Klinkert WE, Ellwart JW, Bradl M, Krivacic K, Lassmann H, Ransohoff RM, Volk HD, Wekerle H, Linington C, Flügel A - J. Exp. Med. (2004)

Bottom Line: Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue.However, exclusively highly pathogenic T cells were significantly reactivated within the CNS.Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Max-Planck Institute for Neurobiology, 82152 Martinsried, Germany.

ABSTRACT
The clinical picture of experimental autoimmune encephalomyelitis (EAE) is critically dependent on the nature of the target autoantigen and the genetic background of the experimental animals. Potentially lethal EAE is mediated by myelin basic protein (MBP)-specific T cells in Lewis rats, whereas transfer of S100beta- or myelin oligodendrocyte glycoprotein (MOG)-specific T cells causes intense inflammatory response in the central nervous system (CNS) with minimal disease. However, in Dark Agouti rats, the pathogenicity of MOG-specific T cells resembles the one of MBP-specific T cells in the Lewis rat. Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue. Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein(+) T cells into the CNS were similar. However, exclusively highly pathogenic T cells were significantly reactivated within the CNS. Without local effector T cell activation, production of monocyte chemoattractants was insufficient to initiate and propagate a full inflammatory response. Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

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Related in: MedlinePlus

IFNγ, IL-10, and IL-2R mRNA of TGFP cells within the CNS. mRNAs of TMBP-GFP and TS100β-GFP cells from spleens (SPL) and spinal cords (CNS) 84 h after transfer and from parallel cultures (CUL) were quantitatively analyzed for the expression of IL-2, IFNγ, IL-10, and IL-2R. TMBP-GFP cells (blue columns), but not TS100β-GFP cells (orange columns), up-regulated the expression of IFNγ, IL-10, and IL-2R upon infiltration into the spinal cord. Specific copies of mRNA in relation to the housekeeping β-actin mRNA are shown. Ex vivo TGFP cells were obtained from three animals and measured in two independent quantitative PCR reactions.
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fig4: IFNγ, IL-10, and IL-2R mRNA of TGFP cells within the CNS. mRNAs of TMBP-GFP and TS100β-GFP cells from spleens (SPL) and spinal cords (CNS) 84 h after transfer and from parallel cultures (CUL) were quantitatively analyzed for the expression of IL-2, IFNγ, IL-10, and IL-2R. TMBP-GFP cells (blue columns), but not TS100β-GFP cells (orange columns), up-regulated the expression of IFNγ, IL-10, and IL-2R upon infiltration into the spinal cord. Specific copies of mRNA in relation to the housekeeping β-actin mRNA are shown. Ex vivo TGFP cells were obtained from three animals and measured in two independent quantitative PCR reactions.

Mentions: The activation status of TMBP-GFP and TS100β-GFP cells recovered from the CNS was investigated further by real-time RT-PCR. Activation of rat CD4+ Th-1 TCLs in vitro leads to the rapid up-regulation of cytokines (IL-2, IFNγ, and IL-10) and membrane proteins (OX-40 antigen and IL-2R). We compared the mRNA transcription of IL-2, IFNγ, IL-10, and IL-2R between TMBP-GFP and TS100β-GFP cells cytofluorometrically sorted from either spleen or CNS 4 d after transfer, and the same TCLs maintained in parallel in IL-2–containing cultures (Fig. 4) .


The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis.

Kawakami N, Lassmann S, Li Z, Odoardi F, Ritter T, Ziemssen T, Klinkert WE, Ellwart JW, Bradl M, Krivacic K, Lassmann H, Ransohoff RM, Volk HD, Wekerle H, Linington C, Flügel A - J. Exp. Med. (2004)

IFNγ, IL-10, and IL-2R mRNA of TGFP cells within the CNS. mRNAs of TMBP-GFP and TS100β-GFP cells from spleens (SPL) and spinal cords (CNS) 84 h after transfer and from parallel cultures (CUL) were quantitatively analyzed for the expression of IL-2, IFNγ, IL-10, and IL-2R. TMBP-GFP cells (blue columns), but not TS100β-GFP cells (orange columns), up-regulated the expression of IFNγ, IL-10, and IL-2R upon infiltration into the spinal cord. Specific copies of mRNA in relation to the housekeeping β-actin mRNA are shown. Ex vivo TGFP cells were obtained from three animals and measured in two independent quantitative PCR reactions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211765&req=5

fig4: IFNγ, IL-10, and IL-2R mRNA of TGFP cells within the CNS. mRNAs of TMBP-GFP and TS100β-GFP cells from spleens (SPL) and spinal cords (CNS) 84 h after transfer and from parallel cultures (CUL) were quantitatively analyzed for the expression of IL-2, IFNγ, IL-10, and IL-2R. TMBP-GFP cells (blue columns), but not TS100β-GFP cells (orange columns), up-regulated the expression of IFNγ, IL-10, and IL-2R upon infiltration into the spinal cord. Specific copies of mRNA in relation to the housekeeping β-actin mRNA are shown. Ex vivo TGFP cells were obtained from three animals and measured in two independent quantitative PCR reactions.
Mentions: The activation status of TMBP-GFP and TS100β-GFP cells recovered from the CNS was investigated further by real-time RT-PCR. Activation of rat CD4+ Th-1 TCLs in vitro leads to the rapid up-regulation of cytokines (IL-2, IFNγ, and IL-10) and membrane proteins (OX-40 antigen and IL-2R). We compared the mRNA transcription of IL-2, IFNγ, IL-10, and IL-2R between TMBP-GFP and TS100β-GFP cells cytofluorometrically sorted from either spleen or CNS 4 d after transfer, and the same TCLs maintained in parallel in IL-2–containing cultures (Fig. 4) .

Bottom Line: Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue.However, exclusively highly pathogenic T cells were significantly reactivated within the CNS.Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Max-Planck Institute for Neurobiology, 82152 Martinsried, Germany.

ABSTRACT
The clinical picture of experimental autoimmune encephalomyelitis (EAE) is critically dependent on the nature of the target autoantigen and the genetic background of the experimental animals. Potentially lethal EAE is mediated by myelin basic protein (MBP)-specific T cells in Lewis rats, whereas transfer of S100beta- or myelin oligodendrocyte glycoprotein (MOG)-specific T cells causes intense inflammatory response in the central nervous system (CNS) with minimal disease. However, in Dark Agouti rats, the pathogenicity of MOG-specific T cells resembles the one of MBP-specific T cells in the Lewis rat. Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue. Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein(+) T cells into the CNS were similar. However, exclusively highly pathogenic T cells were significantly reactivated within the CNS. Without local effector T cell activation, production of monocyte chemoattractants was insufficient to initiate and propagate a full inflammatory response. Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

Show MeSH
Related in: MedlinePlus