Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on α4 integrin

被引：90

作者：

Ifergan, Igal ^{[2
]}

Kebir, Hania ^{[2
]}

Alvarez, Jorge I. ^{[2
]}

Marceau, Gabriel ^{[3
]}

Bernard, Monique ^{[2
]}

Bourbonniere, Lyne ^{[2
]}

Poirier, Josee ^{[1
]}

Duquette, Pierre ^{[1
]}

Talbot, Pierre J. ^{[3
]}

Arbour, Nathalie ^{[2
]}

Prat, Alexandre ^{[1
,2
]}

机构：

[1] CHUM Notre Dame Hosp, Multiple Sclerosis Clin, Dept Neurol, Fac Med, Montreal, PQ H2L 4M1, Canada

[2] Univ Montreal, Neuroimmunol Res Unit, Ctr Excellence Neur, CRCHUM Notre Dame Hosp, Montreal, PQ H2L 4M1, Canada

[3] INRS Inst Armand Frappier, Lab Neuroimmunovirol, Laval, PQ H7V 1B7, Canada

来源：

BRAIN | 2011年 / 134卷

基金：

加拿大健康研究院;

关键词：

multiple sclerosis; blood-brain barrier; CD8(+) T lymphocytes; alpha-4; integrin; migration; BRAIN ENDOTHELIAL-CELLS; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MURINE CORONAVIRUS INFECTION; MULTIPLE-SCLEROSIS PATIENTS; JC VIRUS EPITOPE; TRANSENDOTHELIAL MIGRATION; LEUKOCYTE MIGRATION; IMMUNE SURVEILLANCE;

D O I：

10.1093/brain/awr268

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Clonally expanded CD8(+) T lymphocytes are present in multiple sclerosis lesions, as well as in the cerebrospinal fluid of patients with multiple sclerosis. In experimental autoimmune encephalomyelitis, CD8(+) T lymphocytes are found in spinal cord and brainstem lesions. However, the exact phenotype of central nervous system-infiltrating CD8(+) T lymphocytes and the mechanism by which these cells cross the blood-brain barrier remain largely unknown. Using cerebrospinal fluid from patients with multiple sclerosis, spinal cord from experimental autoimmune encephalomyelitis and coronavirus-induced encephalitis, we demonstrate that central nervous system-infiltrating CD8(+) T lymphocytes are mostly of the effector memory phenotype (CD62L(-) CCR7(-) granzymeB(hi)). We further show that purified human effector memory CD8(+) T lymphocytes transmigrate more readily across blood-brain barrier-endothelial cells than non-effector memory CD8(+) T lymphocytes, and that blood-brain barrier endothelium promotes the selective recruitment of effector memory CD8(+) T lymphocytes. Furthermore, we provide evidence for the recruitment of interferon-gamma- and interleukin-17-secreting CD8(+) T lymphocytes by human and mouse blood-brain barrier endothelium. Finally, we show that in vitro migration of CD8(+) T lymphocytes across blood-brain barrier-endothelial cells is dependent on alpha 4 integrin, but independent of intercellular adhesion molecule-1/leucocyte function-associated antigen-1, activated leucocyte cell adhesion molecule/CD6 and the chemokine monocyte chemotactic protein-1/CCL2. We also demonstrate that in vivo neutralization of very late antigen-4 restricts central nervous system infiltration of CD8(+) T lymphocytes in active immunization and adoptive transfer experimental autoimmune encephalomyelitis, and in coronavirus-induced encephalitis. Our study thus demonstrates an active role of the blood-brain barrier in the recruitment of effector memory CD8(+) T lymphocytes to the CNS compartment and defines alpha 4 integrin as a major contributor of CD8(+) T lymphocyte entry into the brain.

引用

页码：3557 / 3574

页数：18

共 82 条

[81] Immune regulatory CNS-reactive CD8+T cells in experimental autoimmune encephalomyelitis [J].