The extravasation of myelin-specific CD4⁺ T cells from the blood into the central nervous system (CNS) is a crucial factor in the pathogenesis of multiple sclerosis. We know much about how leukocytes traverse the endothelial cell monolayer of post-capillary venules, but far less is known about how they cross the underlying basement membrane, which is the rate-limiting step in transmigration. Recent research indicates a role for basement membrane laminins in specifically regulating the migration of CD4⁺ T cells into the CNS, which could lead to more specific therapies for multiple sclerosis.

Endothelial basement membranes are characterized by laminin 411 (composed of 4, 1 and 1 chains) and laminin 511 (composed of 5, 1 and 1 chains), with uniform distribution of laminin 4 but patchy distribution of laminin 5. Leukocyte extravasation preferentially occurs at laminin 4^hi laminin 5^low sites; to investigate the role of basement membrane laminins in regulating this process, the authors studied laminin 4-deficient (Lama4^-/-) mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis.

Lama4^-/- mice have compensatory ubiquitous expression of laminin 5 along all blood vessels but otherwise have normal expression of adhesion molecules and junctional proteins. After immunization with myelin oligodendrocyte glycoprotein (MOG), Lama4^-/- mice had decreased EAE susceptibility and severity, which correlated with decreased numbers of CD4⁺ T cells in the CNS. Lama4^-/- mice that received wild-type bone marrow also had decreased EAE incidence and severity after MOG immunization, which excludes an immune cell defect. Indeed, Lama4^-/- mice had normal infiltration of leukocytes into peripheral tissues and normal levels of T cell proliferation. A specific defect in the migration of T cells across post-capillary venules in the CNS was confirmed by the transfer of wild-type encephalitogenic T cells to Lama4^-/- or wild-type recipients. Three days after transfer (before T cell proliferation has begun), Lama4^-/- mice had the same number of peripheral donor T cells but significantly lower numbers of donor T cells in the CNS compared with wild-type recipients, which resulted in decreased incidence and severity of EAE.

In in vitro transwell assays, T cells migrated extensively across laminin 411 but not across laminin 511. Antibodies specific for 61 integrin, which is the main receptor for laminin 4 expressed by T cells, inhibited transmigration across laminin 411, as did increasing levels of laminin 511 in a dose-dependent manner. These data indicate that laminin 5 inhibits 61 integrin-mediated T cell migration across laminin 4. 6 integrin-deficient (Itga6^-/-) bone marrow-chimeric mice had decreased EAE severity after MOG immunization, and a similar effect resulted from antibody-mediated blockade of 6 integrin.

As the 61 integrin-mediated migration across laminin 4 seems to preferentially occur for CD4⁺ T cells and not CD8⁺ T cells, macrophages or dendritic cells, targeting this interaction could provide a more specific therapeutic strategy for multiple sclerosis to inhibit CD4⁺ T cell-mediated neurodestruction without compromising other immune responses.

Author: Kirsty Minton - Copyright © 2009 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission