Journal
JOURNAL OF IMMUNOLOGY
Volume 189, Issue 10, Pages 5057-5065Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1202026
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Funding
- Research Grant on Super Special Consortia for Supporting the Development of Cutting-Edge Medical Care from Cabinet Office, Government of Japan
- Japan Society for the Promotion of Science [18189009]
- Ministry of Health, Labor and Welfare of Japan
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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-gamma. 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-gamma and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2(+) CCR5(+) CCR6(-) Th1 cells play a crucial role in the pathogenesis of MS. The Journal of Immunology, 2012, 189: 5057-5065.
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