Endothelial basement membrane laminin alpha5 selectively inhibits T lymphocyte extravasation into the brain.
Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin alpha4 and small amounts of laminin alpha5. In mice lacking laminin alpha4, laminin alpha5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin alpha5 directly inhibited integrin alpha(6)beta(1)-mediated migration of T lymphocytes through laminin alpha4. The data indicate that T lymphocytes use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population.
Wu
Chuan
C
Institute for Physiological Chemistry and Pathobiochemistry, Münster University, Germany.
Ivars
Fredrik
F
Anderson
Per
P
Hallmann
Rupert
R
Vestweber
Dietmar
D
Nilsson
Per
P
Robenek
Horst
H
Tryggvason
Karl
K
Song
Jian
J
Korpos
Eva
E
Loser
Karin
K
Beissert
Stefan
S
Georges-Labouesse
Elisabeth
E
Sorokin
Lydia M
LM
D000818:Animals; D001485:Basement Membrane / Q000502:physiology*; D001921:Brain / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D007797:Laminin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology
C501369:LAMA4 protein, human; C501370:Lama4 protein, mouse; D007797:Laminin; C097043:laminin alpha5