Squeezing Through with Sema3A

Science Signaling  06 Jul 2010:
Vol. 3, Issue 129, pp. ec204
DOI: 10.1126/scisignal.3129ec204

After exposure to antigen in peripheral tissues, dendritic cells (DCs) enter the lymphatic vessels and migrate to lymphoid organs to present antigen to T cells and initiate the T cell response. Semaphorins, initially known for their role in axonal guidance, also function in the immune response. Noting that mice lacking the semaphorin receptor plexin-A1, which is present on DCs, show impaired generation of antigen-specific T cells, Takamatsu et al. compared the response of ovalbumin (OVA)–specific T cells to subcutaneous OVA peptides in wild-type and Plxna1–/– mice and found a decreased proliferative response in the latter. OVA-pulsed DCs from Plxna1–/– mice injected into the footpads of wild-type mice showed impaired migration and decreased localization to lymph nodes compared to DCs from wild-type mice, and Plxna1–/– mice showed decreased lymph node accumulation of endogenous DCs with inflammation. Whereas Plxna1–/– DCs failed to show defects in antigen uptake or in the ability to migrate to chemokines, Plxna1–/– DCs accumulated along the lymphatic vessels when injected intradermally in oxazolone-sensitized mice and also showed impaired transmigration across lymphatic endothelial monolayers in vitro. Plexin-A1 is a component of receptors for the semaphorins Sema3A, Sema6C, and Sema6D, and wild-type DCs showed defective migration when adoptively transferred into Sema3a–/– mice but not Sema6c–/– or Sema6d–/– mice. Sema3A failed to elicit DC migration in Transwell chambers in the absence of chemokines; however, it enhanced migration to the chemokine CCL21 when present in the chamber from which the DCs were migrating (the chamber lacking chemokine). Consistent with this, confocal imaging indicated that plexin-A1 localized to the trailing edge of migrating DCs. Myosin II and the Rho kinase ROCK have been implicated in DC migration, with myosin II thought to enable cells to squeeze through narrow gaps, and Sema3A enhanced myosin light chain (MLC) phosphorylation in wild-type DCs but not Plxna1–/– DCs. Moreover, pharmacological inhibition of myosin II or of ROCK blocked Sema3-induced DC migration across endothelial cell monolayers or through collagen matrices. The authors thus conclude that Sema3A promotes DC entry into the lymphatics through a mechanism involving activation of ROCK- and myosin-dependent contraction.

H. Takamatsu, N. Takegahara, Y. Nakagawa, M. Tomura, M. Taniguchi, R. H. Friedel, H. Rayburn, M. Tessier-Lavigne, Y. Yoshida, T. Okuno, M. Mizui, S. Kang, S. Nojima, T. Tsujimura, Y. Nakatsuji, I. Katayama, T. Toyofuku, H. Kikutani, A. Kumanogoh, Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nat. Immunol. 11, 594–600 (2010). [PubMed]