Dynamin 2 regulates T cell activation by controlling actin polymerization at the immunological synapse

Abstract

Actin reorganization at the immunological synapse is required for the amplification and generation of a functional immune response. Using small interfering RNA, we show here that dynamin 2 (Dyn2), a large GTPase involved in receptor-mediated internalization, did not alter antibody-mediated T cell receptor internalization but considerably affected T cell receptor–stimulated T cell activation by regulating multiple biochemical signaling pathways and the accumulation of F-actin at the immunological synapse. Moreover, Dyn2 interacted directly with the Rho family guanine nucleotide exchange factor Vav1, and this interaction was required for T cell activation. These data identify a functionally important interaction between Dyn2 and Vav1 that regulates actin reorganization and multiple signaling pathways in T lymphocytes.

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Figure 1: Dyn2 is recruited to the T cell–APC contact site.
Figure 2: Dyn2 regulates T cell activation.
Figure 3: TCR expression and antibody-mediated internalization are not altered in Dyn2 suppressed cells.
Figure 4: Dynamin2 suppression inhibits actin polarization at the T cell–APC contact site.
Figure 5: The Dyn2 PRD is required for T cell activation.
Figure 6: The Dyn2 PRD specifically, directly and functionally interacts with the C-terminal SH3 domain of Vav1.
Figure 7: Dyn2 couples TCR signaling to the activation of Erk, Jnk and PLC-γ1.

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Acknowledgements

The authors thank P.J. Leibson for critical reading of the manuscript. Supported by the Mayo Foundation, US National Institutes of Health (AI44959 to D.J.M., and CA47752 to D.D.B.) and Cancer Research Institute (D.D.B.).

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Correspondence to Daniel D Billadeau.

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Supplementary information

Supplementary Fig. 1

Dyn2 suppression does not affect proximal TCR signaling events. (PDF 142 kb)

Supplementary Fig. 2

Verification of the Vav1-Dyn2 interaction. (PDF 101 kb)

Supplementary Fig. 3

PLCγ1, SLP-76 and Sos1 are effectively recruited to LAT in the absence of Dyn2. (PDF 200 kb)

Supplementary Fig. 4

Dyn2 requires Vav1 for efficient localization to the IS. (PDF 236 kb)

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Gomez, T., Hamann, M., McCarney, S. et al. Dynamin 2 regulates T cell activation by controlling actin polymerization at the immunological synapse. Nat Immunol 6, 261–270 (2005). https://doi.org/10.1038/ni1168

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