Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0808505 on December 18, 2008

Published online before print December 18, 2008
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(Journal of Leukocyte Biology. 2009;85:526-538.)
© 2009 by Society for Leukocyte Biology

Antigen-independent adhesion and cell spreading by inducible costimulator engagement inhibits T cell migration in a PI-3K-dependent manner

Jennifer L. Franko* and Alan D. Levine*,{dagger},{ddagger},§,||,1

* Departments of Pathology,
{dagger} Medicine,
{ddagger} Surgery, and
§ Pharmacology and the
|| Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

1 Correspondence: Department of Medicine, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106-4952, USA. E-mail: alan.levine{at}case.edu

Engagement of the costimulatory protein ICOS activates effector/memory T cells in tissue by enhancing TCR-mediated proliferation and cytokine production. We now report that in an antigen-independent manner, ICOS also induces adhesion and spreading in human effector/memory T cells, consequently inhibiting cell migration. T cell spreading and elongation after ICOS ligation are accompanied by the formation of two types of actin-rich membrane protrusions: thin, finger-like structures similar to filopodia and short, discrete microspikes. Although filopodia/microspike formation occurs independently of the PI-3K signaling cascade, ICOS-mediated T cell elongation depends on PI-3K activity, which inhibits the accumulation of GTP-bound RhoA. Further inhibition of RhoA activation exacerbates the ICOS-mediated, elongated phenotype. We propose that in inflamed tissue, ICOS engagement by ICOS ligand on a professional or nonprofessional APC prevents the forward motility of the T cell by inhibiting RhoA-dependent uropod retraction. The resulting ICOS-induced T cell spreading and filopodia/microspike formation may promote antigen recognition by enhancing a T cell’s scanning potential of an adherent APC surface.

Key Words: signal transduction • human • Rho-GTPases • filopodia • microspikes




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