Loss of ​beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype

Vicky Louise Morrison, Martyn John James, Katarzyna Grzes, Peter Cook, David Gavin Glass, Terhi Savinko, Hwee San Lek, Christian Gawden-Bone, Colin Watts, Owain Richard Millington, Andrew Scott MacDonald, Susanna Carola Fagerholm

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Abstract

The actin cytoskeleton has been reported to restrict signalling in resting immune cells. Beta2-integrins, which mediate adhesion and cytoskeletal organization, are emerging as negative regulators of myeloid cell-mediated immune responses, but the molecular mechanisms involved are poorly understood. Here, we show that loss of the interaction between beta2-integrins and kindlin-3 abolishes the actin-linkage of integrins and the GM-CSF receptor in dendritic cells. This leads to increased GM-CSF receptor/Syk signalling, and to the induction of a transcriptional programme characteristic of mature, migratory dendritic cells, accumulation of migratory dendritic cells in lymphoid organs, and increased Th1 immune responses in vivo. We observe increased GM-CSF responses and increased survival in neutrophils where the interaction between integrin and the cytoskeleton is disrupted. Thus, ligand-reinforced beta2-integrin tail interactions restrict cytokine receptor signalling, survival, maturation and migration in myeloid cells and thereby contribute to immune homeostasis in vivo.

Original languageEnglish
Article number5359
Number of pages13
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 28 Oct 2014

Keywords

  • immunology
  • actin cytoskeleton
  • dendritic cells

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    Morrison, V. L., James, M. J., Grzes, K., Cook, P., Glass, D. G., Savinko, T., ... Fagerholm, S. C. (2014). Loss of ​beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype. Nature Communications, 5, [5359]. https://doi.org/10.1038/ncomms6359