Limits...
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.

Show MeSH

Related in: MedlinePlus

Infiltration of W3/13+ and ED1+ cells in the course of tEAE induced by TMBP-GFP, TS100β-GFP, TDA-MOG-GFP, and TLE-MOG-GFP cells. Lesions in the lumbosacral spinal cord 4 d after transfer of TMBP-GFP (A and E), TS100β-GFP (B and F), TDA-MOG-GFP (C and G), and TLE-MOG-GFP (D and H) cells mediated by tEAE are shown. TGFP cells (green), immunohistochemical staining with T cell marker W3/13 (A–D, red), and monocyte/macrophage marker ED1 (E–H, red). (Arrowheads) Location of TGFP cells (A–D) and monocytes/macrophages (E–H). Magnification bars, 10 μm. TGFP cells of all specificities infiltrate the CNS in high numbers at the onset of clinical symptoms. They can be found as well in the meningeal and perivascular areas as deep as the CNS parenchyma (A–H). ED-1–positive macrophages in TMBP-GFP and TDA-MOG-GFP cell–tEAE enter the CNS in high numbers where they are distributed throughout the tissue (E and G). In contrast, TS100β-GFP and TLE-MOG-GFP cells recruit less ED1+ monocytes/macrophages, which are mainly restricted to the meningeal and perivascular areas (F and H). Representative histological sections of lumbo-sacral spinal cords of at least two independent experiments/TCLs are shown.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211765&req=5

fig2: Infiltration of W3/13+ and ED1+ cells in the course of tEAE induced by TMBP-GFP, TS100β-GFP, TDA-MOG-GFP, and TLE-MOG-GFP cells. Lesions in the lumbosacral spinal cord 4 d after transfer of TMBP-GFP (A and E), TS100β-GFP (B and F), TDA-MOG-GFP (C and G), and TLE-MOG-GFP (D and H) cells mediated by tEAE are shown. TGFP cells (green), immunohistochemical staining with T cell marker W3/13 (A–D, red), and monocyte/macrophage marker ED1 (E–H, red). (Arrowheads) Location of TGFP cells (A–D) and monocytes/macrophages (E–H). Magnification bars, 10 μm. TGFP cells of all specificities infiltrate the CNS in high numbers at the onset of clinical symptoms. They can be found as well in the meningeal and perivascular areas as deep as the CNS parenchyma (A–H). ED-1–positive macrophages in TMBP-GFP and TDA-MOG-GFP cell–tEAE enter the CNS in high numbers where they are distributed throughout the tissue (E and G). In contrast, TS100β-GFP and TLE-MOG-GFP cells recruit less ED1+ monocytes/macrophages, which are mainly restricted to the meningeal and perivascular areas (F and H). Representative histological sections of lumbo-sacral spinal cords of at least two independent experiments/TCLs are shown.

Mentions: Invasion of GFP-expressing effector T cells into the CNS was verified by confocal immunofluorescence microscopy. Beyond confirming the FACS® data, morphology showed similar migration patterns for all types of neuroantigen-specific GFP+ cells. The majority of cells did not remain in the perivascular space, but penetrated deeply into the parenchyma (Fig. 2 and Table II). Therefore, the inability of TS100β-GFP and TMOG-GFP cells to induce a significant neurological deficit in the Lewis rat cannot be attributed to a failure to cross the blood brain barrier (BBB) and infiltrate into the target tissue.


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)

Infiltration of W3/13+ and ED1+ cells in the course of tEAE induced by TMBP-GFP, TS100β-GFP, TDA-MOG-GFP, and TLE-MOG-GFP cells. Lesions in the lumbosacral spinal cord 4 d after transfer of TMBP-GFP (A and E), TS100β-GFP (B and F), TDA-MOG-GFP (C and G), and TLE-MOG-GFP (D and H) cells mediated by tEAE are shown. TGFP cells (green), immunohistochemical staining with T cell marker W3/13 (A–D, red), and monocyte/macrophage marker ED1 (E–H, red). (Arrowheads) Location of TGFP cells (A–D) and monocytes/macrophages (E–H). Magnification bars, 10 μm. TGFP cells of all specificities infiltrate the CNS in high numbers at the onset of clinical symptoms. They can be found as well in the meningeal and perivascular areas as deep as the CNS parenchyma (A–H). ED-1–positive macrophages in TMBP-GFP and TDA-MOG-GFP cell–tEAE enter the CNS in high numbers where they are distributed throughout the tissue (E and G). In contrast, TS100β-GFP and TLE-MOG-GFP cells recruit less ED1+ monocytes/macrophages, which are mainly restricted to the meningeal and perivascular areas (F and H). Representative histological sections of lumbo-sacral spinal cords of at least two independent experiments/TCLs are shown.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Infiltration of W3/13+ and ED1+ cells in the course of tEAE induced by TMBP-GFP, TS100β-GFP, TDA-MOG-GFP, and TLE-MOG-GFP cells. Lesions in the lumbosacral spinal cord 4 d after transfer of TMBP-GFP (A and E), TS100β-GFP (B and F), TDA-MOG-GFP (C and G), and TLE-MOG-GFP (D and H) cells mediated by tEAE are shown. TGFP cells (green), immunohistochemical staining with T cell marker W3/13 (A–D, red), and monocyte/macrophage marker ED1 (E–H, red). (Arrowheads) Location of TGFP cells (A–D) and monocytes/macrophages (E–H). Magnification bars, 10 μm. TGFP cells of all specificities infiltrate the CNS in high numbers at the onset of clinical symptoms. They can be found as well in the meningeal and perivascular areas as deep as the CNS parenchyma (A–H). ED-1–positive macrophages in TMBP-GFP and TDA-MOG-GFP cell–tEAE enter the CNS in high numbers where they are distributed throughout the tissue (E and G). In contrast, TS100β-GFP and TLE-MOG-GFP cells recruit less ED1+ monocytes/macrophages, which are mainly restricted to the meningeal and perivascular areas (F and H). Representative histological sections of lumbo-sacral spinal cords of at least two independent experiments/TCLs are shown.
Mentions: Invasion of GFP-expressing effector T cells into the CNS was verified by confocal immunofluorescence microscopy. Beyond confirming the FACS® data, morphology showed similar migration patterns for all types of neuroantigen-specific GFP+ cells. The majority of cells did not remain in the perivascular space, but penetrated deeply into the parenchyma (Fig. 2 and Table II). Therefore, the inability of TS100β-GFP and TMOG-GFP cells to induce a significant neurological deficit in the Lewis rat cannot be attributed to a failure to cross the blood brain barrier (BBB) and infiltrate into the target tissue.

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