CD8+ T cells cause disability and axon loss in a mouse model of multiple sclerosis

Chandra Deb, Reghann G. Lafrance-Corey, William F. Schmalstieg, Brian M. Sauer, Huan D Wang, Christopher L. German, Anthony John Windebank, Moses Rodriguez, Charles L Howe

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background: The objective of this study was to test the hypothesis that CD8+ T cells directly mediate motor disability and axon injury in the demyelinated central nervous system. We have previously observed that genetic deletion of the CD8+ T cell effector molecule perforin leads to preservation of motor function and preservation of spinal axons in chronically demyelinated mice. Methodology/Principal Findings: To determine if CD8+ T cells are necessary and sufficient to directly injure demyelinated axons, we adoptively transferred purified perforin-competent CD8+ spinal cord-infiltrating T cells into profoundly demyelinated but functionally preserved perforin-deficient host mice. Transfer of CD8+ spinal cord-infiltrating T cells rapidly and irreversibly impaired motor function, disrupted spinal cord motor conduction, and reduced the number of mediumand large-caliber spinal axons. Likewise, immunodepletion of CD8+ T cells from chronically demyelinated wildtype mice preserved motor function and limited axon loss without altering other disease parameters. Conclusions/Significance: In multiple sclerosis patients, CD8+ T cells outnumber CD4+ T cells in active lesions and the number of CD8+ T cells correlates with the extent of ongoing axon injury and functional disability. Our findings suggest that CD8+ T cells may directly injure demyelinated axons and are therefore a viable therapeutic target to protect axons and motor function in patients with multiple sclerosis.

Original languageEnglish (US)
Article numbere12478
JournalPLoS One
Volume5
Issue number8
DOIs
StatePublished - 2010

Fingerprint

T-cells
sclerosis
axons
Multiple Sclerosis
Axons
T-lymphocytes
animal models
T-Lymphocytes
Perforin
spinal cord
Spinal Cord
mice
Wounds and Injuries
Neurology
lesions (animal)
central nervous system
Central Nervous System
therapeutics
Molecules

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

CD8+ T cells cause disability and axon loss in a mouse model of multiple sclerosis. / Deb, Chandra; Lafrance-Corey, Reghann G.; Schmalstieg, William F.; Sauer, Brian M.; Wang, Huan D; German, Christopher L.; Windebank, Anthony John; Rodriguez, Moses; Howe, Charles L.

In: PLoS One, Vol. 5, No. 8, e12478, 2010.

Research output: Contribution to journalArticle

Deb, C, Lafrance-Corey, RG, Schmalstieg, WF, Sauer, BM, Wang, HD, German, CL, Windebank, AJ, Rodriguez, M & Howe, CL 2010, 'CD8+ T cells cause disability and axon loss in a mouse model of multiple sclerosis', PLoS One, vol. 5, no. 8, e12478. https://doi.org/10.1371/journal.pone.0012478
Deb, Chandra ; Lafrance-Corey, Reghann G. ; Schmalstieg, William F. ; Sauer, Brian M. ; Wang, Huan D ; German, Christopher L. ; Windebank, Anthony John ; Rodriguez, Moses ; Howe, Charles L. / CD8+ T cells cause disability and axon loss in a mouse model of multiple sclerosis. In: PLoS One. 2010 ; Vol. 5, No. 8.
@article{9262ddcbb0e0424ca9fdd4c6c83b6ebc,
title = "CD8+ T cells cause disability and axon loss in a mouse model of multiple sclerosis",
abstract = "Background: The objective of this study was to test the hypothesis that CD8+ T cells directly mediate motor disability and axon injury in the demyelinated central nervous system. We have previously observed that genetic deletion of the CD8+ T cell effector molecule perforin leads to preservation of motor function and preservation of spinal axons in chronically demyelinated mice. Methodology/Principal Findings: To determine if CD8+ T cells are necessary and sufficient to directly injure demyelinated axons, we adoptively transferred purified perforin-competent CD8+ spinal cord-infiltrating T cells into profoundly demyelinated but functionally preserved perforin-deficient host mice. Transfer of CD8+ spinal cord-infiltrating T cells rapidly and irreversibly impaired motor function, disrupted spinal cord motor conduction, and reduced the number of mediumand large-caliber spinal axons. Likewise, immunodepletion of CD8+ T cells from chronically demyelinated wildtype mice preserved motor function and limited axon loss without altering other disease parameters. Conclusions/Significance: In multiple sclerosis patients, CD8+ T cells outnumber CD4+ T cells in active lesions and the number of CD8+ T cells correlates with the extent of ongoing axon injury and functional disability. Our findings suggest that CD8+ T cells may directly injure demyelinated axons and are therefore a viable therapeutic target to protect axons and motor function in patients with multiple sclerosis.",
author = "Chandra Deb and Lafrance-Corey, {Reghann G.} and Schmalstieg, {William F.} and Sauer, {Brian M.} and Wang, {Huan D} and German, {Christopher L.} and Windebank, {Anthony John} and Moses Rodriguez and Howe, {Charles L}",
year = "2010",
doi = "10.1371/journal.pone.0012478",
language = "English (US)",
volume = "5",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - CD8+ T cells cause disability and axon loss in a mouse model of multiple sclerosis

AU - Deb, Chandra

AU - Lafrance-Corey, Reghann G.

AU - Schmalstieg, William F.

AU - Sauer, Brian M.

AU - Wang, Huan D

AU - German, Christopher L.

AU - Windebank, Anthony John

AU - Rodriguez, Moses

AU - Howe, Charles L

PY - 2010

Y1 - 2010

N2 - Background: The objective of this study was to test the hypothesis that CD8+ T cells directly mediate motor disability and axon injury in the demyelinated central nervous system. We have previously observed that genetic deletion of the CD8+ T cell effector molecule perforin leads to preservation of motor function and preservation of spinal axons in chronically demyelinated mice. Methodology/Principal Findings: To determine if CD8+ T cells are necessary and sufficient to directly injure demyelinated axons, we adoptively transferred purified perforin-competent CD8+ spinal cord-infiltrating T cells into profoundly demyelinated but functionally preserved perforin-deficient host mice. Transfer of CD8+ spinal cord-infiltrating T cells rapidly and irreversibly impaired motor function, disrupted spinal cord motor conduction, and reduced the number of mediumand large-caliber spinal axons. Likewise, immunodepletion of CD8+ T cells from chronically demyelinated wildtype mice preserved motor function and limited axon loss without altering other disease parameters. Conclusions/Significance: In multiple sclerosis patients, CD8+ T cells outnumber CD4+ T cells in active lesions and the number of CD8+ T cells correlates with the extent of ongoing axon injury and functional disability. Our findings suggest that CD8+ T cells may directly injure demyelinated axons and are therefore a viable therapeutic target to protect axons and motor function in patients with multiple sclerosis.

AB - Background: The objective of this study was to test the hypothesis that CD8+ T cells directly mediate motor disability and axon injury in the demyelinated central nervous system. We have previously observed that genetic deletion of the CD8+ T cell effector molecule perforin leads to preservation of motor function and preservation of spinal axons in chronically demyelinated mice. Methodology/Principal Findings: To determine if CD8+ T cells are necessary and sufficient to directly injure demyelinated axons, we adoptively transferred purified perforin-competent CD8+ spinal cord-infiltrating T cells into profoundly demyelinated but functionally preserved perforin-deficient host mice. Transfer of CD8+ spinal cord-infiltrating T cells rapidly and irreversibly impaired motor function, disrupted spinal cord motor conduction, and reduced the number of mediumand large-caliber spinal axons. Likewise, immunodepletion of CD8+ T cells from chronically demyelinated wildtype mice preserved motor function and limited axon loss without altering other disease parameters. Conclusions/Significance: In multiple sclerosis patients, CD8+ T cells outnumber CD4+ T cells in active lesions and the number of CD8+ T cells correlates with the extent of ongoing axon injury and functional disability. Our findings suggest that CD8+ T cells may directly injure demyelinated axons and are therefore a viable therapeutic target to protect axons and motor function in patients with multiple sclerosis.

UR - http://www.scopus.com/inward/record.url?scp=77957945751&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957945751&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0012478

DO - 10.1371/journal.pone.0012478

M3 - Article

C2 - 20814579

AN - SCOPUS:77957945751

VL - 5

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e12478

ER -