CCR2(+)CCR5(+) T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis.
Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4(+) autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS. In this article, we report that CCR2(+)CCR5(+) T cells constitute a unique population selectively enriched in the cerebrospinal fluid of MS patients during relapse but not in patients with other neurologic diseases. After polyclonal stimulation, the CCR2(+)CCR5(+) T cells exhibited a distinct ability to produce matrix metalloproteinase-9 and osteopontin, which are involved in the CNS pathology of MS. Furthermore, after TCR stimulation, the CCR2(+)CCR5(+) T cells showed a higher invasive potential across an in vitro blood-brain barrier model compared with other T cells. Of note, the CCR2(+)CCR5(+) T cells from MS patients in relapse are reactive to myelin basic protein, as assessed by production of IFN-γ. We also demonstrated that the CCR6(-), but not the CCR6(+), population within CCR2(+)CCR5(+) T cells was highly enriched in the cerebrospinal fluid during MS relapse (p < 0.0005) and expressed higher levels of IFN-γ and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2(+)CCR5(+)CCR6(-) Th1 cells play a crucial role in the pathogenesis of MS.
Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
Wakiro
W
Sato
Atsuko
A
Tomita
Daijyu
D
Ichikawa
Youwei
Y
Lin
Hitaru
H
Kishida
Sachiko
S
Miyake
Masafumi
M
Ogawa
Tomoko
T
Okamoto
Miho
M
Murata
Yoshiyuki
Y
Kuroiwa
Toshimasa
T
Aranami
Takashi
T
Yamamura
D000328:Adult; D000368:Aged; D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000276:immunology*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000096:biosynthesis / Q000276:immunology*; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D054399:Receptors, CCR6; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
C515334:CCR2 protein, human; C106311:CCR6 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D054399:Receptors, CCR6; D053495:Osteopontin; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9