Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration

Author:

Morin Nicole A.1,Oakes Patrick W.2,Hyun Young-Min3,Lee Dooyoung4,Chin Y. Eugene1,King Michael R.5,Springer Timothy A.6,Shimaoka Motomu6,Tang Jay X.2,Reichner Jonathan S.1,Kim Minsoo3

Affiliation:

1. Department of Surgery, Rhode Island Hospital and Brown Medical School, Providence, RI 02903

2. Department of Physics, Brown University, Providence, RI 02912

3. Department of Microbiologyand Immunology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester, Rochester, NY 14642

4. Department of Chemical Engineering

5. Department of Biomedical Engineering,

6. The CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115

Abstract

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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