Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS.
TH17 cells enter tissues to facilitate pathogenic autoimmune responses, including multiple sclerosis (MS). However, the adhesion molecules involved in the unique migratory capacity of TH17 cells, into both inflamed and uninflamed tissues remain unclear. Herein, we characterize MCAM (CD146) as an adhesion molecule that defines human TH17 cells in the circulation; following in vitro restimulation of human memory T cells, nearly all of the capacity to secrete IL-17 is contained within the population of cells expressing MCAM. Furthermore, we identify the MCAM ligand as laminin 411, an isoform of laminin expressed within the vascular endothelial basement membranes under inflammatory as well as homeotstatic conditions. Purified MCAM-Fc binds to laminin 411 with an affinity of 27 nM, and recognizes vascular basement membranes in mouse and human tissue. MCAM-Fc binding was undetectable in tissue from mice with targeted deletion of laminin 411, indicating that laminin 411 is a major tissue ligand for MCAM. An anti-MCAM monoclonal antibody, selected for inhibition of laminin binding, as well as soluble MCAM-Fc, inhibited T cell adhesion to laminin 411 in vitro. When administered in vivo, the antibody reduced TH17 cell infiltration into the CNS and ameliorated disease in an animal model of MS. Our data suggest that MCAM and laminin 411 interact to facilitate TH17 cell entry into tissues and promote inflammation.
Elan Pharmaceuticals, San Francisco, California, United States of America. kenneth.flanagan@elan.com
Ken
K
Flanagan
Kent
K
Fitzgerald
Jeanne
J
Baker
Karin
K
Regnstrom
Shyra
S
Gardai
Frederique
F
Bard
Simonetta
S
Mocci
Pui
P
Seto
Monica
M
You
Catherine
C
Larochelle
Alexandre
A
Prat
Samuel
S
Chow
Lauri
L
Li
Chris
C
Vandevert
Wagner
W
Zago
Carlos
C
Lorenzana
Christopher
C
Nishioka
Jennifer
J
Hoffman
Raquel
R
Botelho
Christopher
C
Willits
Kevin
K
Tanaka
Jennifer
J
Johnston
Ted
T
Yednock
D000818:Animals; D051929:CD146 Antigen / Q000378:metabolism; D016466:CHO Cells; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D002831:Choroid Plexus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000502:physiology; D007378:Interleukins / Q000378:metabolism; D007797:Laminin / Q000502:physiology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D058504:Th17 Cells / Q000378:metabolism / Q000502:physiology*; D000097043:Interleukin-22
D051929:CD146 Antigen; D020381:Interleukin-17; D053583:Interleukin-1beta; D007378:Interleukins; D007797:Laminin; D008024:Ligands; D000097043:Interleukin-22; C501369:LAMA4 protein, human; C478221:LAMB1 protein, human; C497902:MCAM protein, human; C089141:laminin gamma 1