Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration.
Precise spatial and temporal regulation of cell adhesion and de-adhesion is critical for dynamic lymphocyte migration. Although a great deal of information has been learned about integrin lymphocyte function-associated antigen (LFA)-1 adhesion, the mechanism that regulates efficient LFA-1 de-adhesion from intercellular adhesion molecule (ICAM)-1 during T lymphocyte migration is unknown. Here, we show that nonmuscle myosin heavy chain IIA (MyH9) is recruited to LFA-1 at the uropod of migrating T lymphocytes, and inhibition of the association of MyH9 with LFA-1 results in extreme uropod elongation, defective tail detachment, and decreased lymphocyte migration on ICAM-1, without affecting LFA-1 activation by chemokine CXCL-12. This defect was reversed by a small molecule antagonist that inhibits both LFA-1 affinity and avidity regulation, but not by an antagonist that inhibits only affinity regulation. Total internal reflection fluorescence microscopy of the contact zone between migrating T lymphocytes and ICAM-1 substrate revealed that inactive LFA-1 is selectively localized to the posterior of polarized T lymphocytes, whereas active LFA-1 is localized to their anterior. Thus, during T lymphocyte migration, uropodal adhesion depends on LFA-1 avidity, where MyH9 serves as a key mechanical link between LFA-1 and the cytoskeleton that is critical for LFA-1 de-adhesion.
Morin
Nicole A
NA
Department of Surgery, Rhode Island Hospital and Brown Medical School, Providence, RI 02903, USA.
Oakes
Patrick W
PW
Hyun
Young-Min
YM
Lee
Dooyoung
D
Chin
Y Eugene
YE
Chin
Eugene Y
EY
King
Michael R
MR
Springer
Timothy A
TA
Shimaoka
Motomu
M
Tang
Jay X
JX
Reichner
Jonathan S
JS
Kim
Minsoo
M
D002460:Cell Line; D002465:Cell Movement; D002469:Cell Separation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D019281:Dimerization; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis*; D018715:Microscopy, Video; D008954:Models, Biological; D020409:Molecular Motor Proteins / Q000096:biosynthesis*; D018995:Myosin Heavy Chains / Q000096:biosynthesis*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D017550:Spectroscopy, Fourier Transform Infrared; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D016169:Lymphocyte Function-Associated Antigen-1; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D034741:RNA, Small Interfering; D018799:Intercellular Adhesion Molecule-1; D018995:Myosin Heavy Chains