Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms6359
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Funding
- BBSRC
- Arthritis Research UK
- Tenovus Scotland
- Anonymous Trust
- Academy of Finland
- Biocentrum Helsinki
- Ella & Georg Ehrnrooth Foundation
- MRC
- BBSRC [BB/G017123/1] Funding Source: UKRI
- MRC [G0701272, G0701437] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G017123/1] Funding Source: researchfish
- Medical Research Council [G0701437, G0701272] Funding Source: researchfish
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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.
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