title: Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on α4 integrin.
abstract: 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-γ- 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 α4 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 α4 integrin as a major contributor of CD8(+) T lymphocyte entry into the brain.
authors: Neuroimmunology Research Unit, Centre for Excellence in Neuromics, CRCHUM-Notre-Dame Hospital, Université de Montréal, Montréal, QC, H2L 4M1, Canada.
authors: Igal
authors: I
authors: Ifergan
authors: Hania
authors: H
authors: Kebir
authors: Jorge I
authors: JI
authors: Alvarez
authors: Gabriel
authors: G
authors: Marceau
authors: Monique
authors: M
authors: Bernard
authors: Lyne
authors: L
authors: Bourbonnière
authors: Josée
authors: J
authors: Poirier
authors: Pierre
authors: P
authors: Duquette
authors: Pierre J
authors: PJ
authors: Talbot
authors: Nathalie
authors: N
authors: Arbour
authors: Alexandre
authors: A
authors: Prat
mesh_terms: D000328:Adult; D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D018352:Coronavirus Infections / Q000276:immunology* / Q000378:metabolism; D018792:Encephalitis, Viral / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D039441:Integrin alpha4 / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism
chemical_list: D039441:Integrin alpha4