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Cutting Edge: Rho Activation and Actin Polarization Are Dependent on Plexin-A1 in Dendritic Cells¹

So-Young Eun^2,, Brian P. O’Connor^2,, Athena W. Wong^2,*,, Hendrick W. van Deventer, Debra J. Taxman, William Reed, Ping Li, Janice S. Blum, Karen P. McKinnon and Jenny P.-Y. Ting^3,*,

^* Curriculum in Genetics and Molecular Biology, Department of Microbiology and Immunology and the Lineberger Comprehensive Cancer Center, and Department of Pediatrics and Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill NC 27599; and Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202

We recently identified expression of the semaphorin receptor, plexin-A1, in dendritic cells (DCs); however, its function in these cells remains to be elucidated. To investigate function and maximize physiological relevance, we devised a retroviral approach to ablate plexin-A1 gene expression using small hairpin RNA (shRNA) in primary bone marrow-derived DCs. We show that plexin-A1 localizes within the cytoplasm of immature DCs, becomes membrane-associated, and is enriched at the immune synapse in mature DCs. Reducing plexin-A1 expression with shRNA greatly reduced actin polarization as well as Rho activation without affecting Rac or Cdc42 activation. A Rho inhibitor, C3, also reduced actin polarization. These changes were accompanied by the near-ablation of T cell activation. We propose a mechanism of adaptive immune regulation in which plexin-A1 controls Rho activation and actin cytoskeletal rearrangements in DCs that is associated with enhanced DC-T cell interactions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI29564. J.P.-Y.T. is a Sandler Program in Asthma Research awardee, and B.P.O is an Irvington Institute Postdoctoral Fellowship awardee.

² S.-Y.E., B.P.O., and A.W.W. contributed equally to this work and should be considered co-first authors.

³ Address correspondence and reprint requests to Dr. Jenny P.-Y. Ting, Lineberger Comprehensive Cancer Center, University of North Carolina, CB7295, Chapel Hill, NC 27599. E-mail address: panyun{at}med.unc.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; MHC-II, MHC class II; PFA, paraformaldehyde.

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