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Immunity. 2015 May 19;42(5):864-76. doi: 10.1016/j.immuni.2015.04.013.

Actin depletion initiates events leading to granule secretion at the immunological synapse.

Author information

1
Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; National Institute of Child Health and Disease, NIH, Bethesda, MD 20892, USA.
2
Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
3
Howard Hughes Medical Institute, Janelia Farm Research Campus, 19700 Helix Drive, Ashburn, VA 20147, USA.
4
National Institute of Child Health and Disease, NIH, Bethesda, MD 20892, USA.
5
National High Magnetic Field Laboratory and Department of Biological Science, Florida State University, Tallahassee, FL 32304, USA.
6
National Institute of Child Health and Disease, NIH, Bethesda, MD 20892, USA. Electronic address: lippincj@mail.nih.gov.
7
Cambridge Institute for Medical Research, University of Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. Electronic address: gg305@cam.ac.uk.

Abstract

Cytotoxic T lymphocytes (CTLs) use polarized secretion to rapidly destroy virally infected and tumor cells. To understand the temporal relationships between key events leading to secretion, we used high-resolution 4D imaging. CTLs approached targets with actin-rich projections at the leading edge, creating an initially actin-enriched contact with rearward-flowing actin. Within 1 min, cortical actin reduced across the synapse, T cell receptors (TCRs) clustered centrally to form the central supramolecular activation cluster (cSMAC), and centrosome polarization began. Granules clustered around the moving centrosome within 2.5 min and reached the synapse after 6 min. TCR-bearing intracellular vesicles were delivered to the cSMAC as the centrosome docked. We found that the centrosome and granules were delivered to an area of membrane with reduced cortical actin density and phospholipid PIP2. These data resolve the temporal order of events during synapse maturation in 4D and reveal a critical role for actin depletion in regulating secretion.

PMID:
25992860
PMCID:
PMC4448150
DOI:
10.1016/j.immuni.2015.04.013
[Indexed for MEDLINE]
Free PMC Article

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