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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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Weakly pathogenic TGFP cells show minimal reactivation after infiltrating the target organ. 84 h after transfer of TMBP-GFP, TDA-MOG-GFP, TS100β-GFP, and TLE-MOG-GFP cells, the spinal cords and spleens of recipient rats were prepared. TGFP cells were analyzed cytofluorometrically for the expression of the surface membrane molecules OX-40 antigen (OX-40), IL-2R, and CD4. (IgG) Isotype control. Shaded histograms represent spleen-derived TGFP cells, and unshaded overlay histograms show TGFP cells isolated simultaneously from the CNS. Spinal cord–derived TMBP-GFP cells (blue histograms) and TDA-MOG-GFP cells (black histograms), but not TS100β-GFP cells (red histograms) and TLE-MOG-GFP cells (yellow histograms), up-regulate OX-40 antigen and IL-2R. Representative data of at least four independent experiments/TCLs are shown.
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fig3: Weakly pathogenic TGFP cells show minimal reactivation after infiltrating the target organ. 84 h after transfer of TMBP-GFP, TDA-MOG-GFP, TS100β-GFP, and TLE-MOG-GFP cells, the spinal cords and spleens of recipient rats were prepared. TGFP cells were analyzed cytofluorometrically for the expression of the surface membrane molecules OX-40 antigen (OX-40), IL-2R, and CD4. (IgG) Isotype control. Shaded histograms represent spleen-derived TGFP cells, and unshaded overlay histograms show TGFP cells isolated simultaneously from the CNS. Spinal cord–derived TMBP-GFP cells (blue histograms) and TDA-MOG-GFP cells (black histograms), but not TS100β-GFP cells (red histograms) and TLE-MOG-GFP cells (yellow histograms), up-regulate OX-40 antigen and IL-2R. Representative data of at least four independent experiments/TCLs are shown.

Mentions: Upon invasion of the CNS, encephalitogenic Lewis TMBP-GFP effector cells underwent reactivation as indicated by increased levels of OX-40 antigen and IL-2R (Fig. 3) and partial down-modulation of the CD3–TCR complex on their surface (not depicted; reference 12). Similar changes were also seen in highly pathogenic TDA-MOG-GFP cells when analyzed isolated from the CNS shortly after onset of EAE 4 d after transfer (Fig. 3). In striking contrast, the weakly pathogenic TS100β-GFP and TLE-MOG-GFP cells that infiltrated the CNS in equally high numbers (Figs. 1 and 2) did not show significant up-regulation of IL-2R and OX-40 antigen (Fig. 3), down-modulation of the CD3–TCR complex (not depicted), nor did they induce clinical disease (Table II).


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)

Weakly pathogenic TGFP cells show minimal reactivation after infiltrating the target organ. 84 h after transfer of TMBP-GFP, TDA-MOG-GFP, TS100β-GFP, and TLE-MOG-GFP cells, the spinal cords and spleens of recipient rats were prepared. TGFP cells were analyzed cytofluorometrically for the expression of the surface membrane molecules OX-40 antigen (OX-40), IL-2R, and CD4. (IgG) Isotype control. Shaded histograms represent spleen-derived TGFP cells, and unshaded overlay histograms show TGFP cells isolated simultaneously from the CNS. Spinal cord–derived TMBP-GFP cells (blue histograms) and TDA-MOG-GFP cells (black histograms), but not TS100β-GFP cells (red histograms) and TLE-MOG-GFP cells (yellow histograms), up-regulate OX-40 antigen and IL-2R. Representative data of at least four independent experiments/TCLs are shown.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Weakly pathogenic TGFP cells show minimal reactivation after infiltrating the target organ. 84 h after transfer of TMBP-GFP, TDA-MOG-GFP, TS100β-GFP, and TLE-MOG-GFP cells, the spinal cords and spleens of recipient rats were prepared. TGFP cells were analyzed cytofluorometrically for the expression of the surface membrane molecules OX-40 antigen (OX-40), IL-2R, and CD4. (IgG) Isotype control. Shaded histograms represent spleen-derived TGFP cells, and unshaded overlay histograms show TGFP cells isolated simultaneously from the CNS. Spinal cord–derived TMBP-GFP cells (blue histograms) and TDA-MOG-GFP cells (black histograms), but not TS100β-GFP cells (red histograms) and TLE-MOG-GFP cells (yellow histograms), up-regulate OX-40 antigen and IL-2R. Representative data of at least four independent experiments/TCLs are shown.
Mentions: Upon invasion of the CNS, encephalitogenic Lewis TMBP-GFP effector cells underwent reactivation as indicated by increased levels of OX-40 antigen and IL-2R (Fig. 3) and partial down-modulation of the CD3–TCR complex on their surface (not depicted; reference 12). Similar changes were also seen in highly pathogenic TDA-MOG-GFP cells when analyzed isolated from the CNS shortly after onset of EAE 4 d after transfer (Fig. 3). In striking contrast, the weakly pathogenic TS100β-GFP and TLE-MOG-GFP cells that infiltrated the CNS in equally high numbers (Figs. 1 and 2) did not show significant up-regulation of IL-2R and OX-40 antigen (Fig. 3), down-modulation of the CD3–TCR complex (not depicted), nor did they induce clinical disease (Table II).

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