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


RESULTS
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 medium- and 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
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.
Deb
Chandra
C
Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
Lafrance-Corey
Reghann G
RG
Schmalstieg
William F
WF
Sauer
Brian M
BM
Wang
Huan
H
German
Christopher L
CL
Windebank
Anthony J
AJ
Rodriguez
Moses
M
Howe
Charles L
CL
D000818:Animals; D001369:Axons / Q000276:immunology* / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003711:Demyelinating Diseases / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006649:Histocompatibility Antigens / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000276:immunology* / Q000502:physiology*; D009044:Motor Cortex / Q000473:pathology; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D054353:Perforin / Q000172:deficiency / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology
D006649:Histocompatibility Antigens; D054353:Perforin
Ann Neurol. 2009 Mar;65(3):239-48
19334069
J Neurovirol. 2001 Oct;7(5):409-20
11582513
Ann Neurol. 1986 Jun;19(6):578-87
3524414
N Engl J Med. 2008 Oct 23;359(17):1786-801
18946064
N Engl J Med. 2006 Mar 2;354(9):899-910
16510744
Nat Med. 1998 Feb;4(2):187-193
9461192
J Neuroimmunol. 2007 Aug;188(1-2):13-21
17493690
Ann Neurol. 2003 May;53(5):680-4
12731006
N Engl J Med. 2009 Sep 10;361(11):1081-7
19741229
Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2428-33
14983026
Lancet Neurol. 2009 Mar;8(3):254-60
19201654
Nat Rev Immunol. 2009 Jun;9(6):393-407
19444307
Curr Drug Targets Inflamm Allergy. 2005 Apr;4(2):239-45
15853746
J Neuroimmunol. 2009 Sep 29;214(1-2):33-42
19596449
Ann Neurol. 2009 Aug;66(2):132-41
19743458
Brain Pathol. 2004 Jan;14(1):43-50
14997936
Brain. 2002 Mar;125(Pt 3):538-50
11872611
Am J Pathol. 2009 Sep;175(3):1160-6
19700745
Neurobiol Dis. 2007 Feb;25(2):354-9
17112732
Lab Invest. 1991 Mar;64(3):358-70
2002654
Brain. 2007 Nov;130(Pt 11):2789-99
17890278
Curr Top Microbiol Immunol. 2008;318:93-131
18219816
J Neurosci. 1998 Sep 15;18(18):7306-14
9736651
J Neuroimmunol. 2008 May 30;196(1-2):159-65
18396337
Brain. 2002 Oct;125(Pt 10):2202-12
12244078
Nat Rev Neurol. 2009 Nov;5(11):591-7
19806149
Eur J Immunol. 2009 Dec;39(12):3423-35
19768696
Brain. 2005 Aug;128(Pt 8):1747-63
15975943
Neurology. 1997 Aug;49(2):351-7
9270561
J Neuropathol Exp Neurol. 2009 Sep;68(9):1037-48
19680139
J Exp Med. 2000 Aug 7;192(3):393-404
10934227