CCR2+CCR5+ T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis

Wakiro Sato, Atsuko Tomita, Daijyu Ichikawa, Youwei Lin, Hitaru Kishida, Sachiko Miyake, Masafumi Ogawa, Tomoko Okamoto, Miho Murata, Yoshiyuki Kuroiwa, Toshimasa Aranami, Takashi Yamamura

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58 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)5057-5065
Number of pages9
JournalJournal of Immunology
Issue number10
Publication statusPublished - 2012 Nov 15
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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