@article {48729,
	title = {Cortical actin recovery at the immunological synapse leads to termination of lytic granule secretion in cytotoxic T lymphocytes.},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {114},
	year = {2017},
	month = {2017 Aug 08},
	pages = {E6585-94},
	abstract = {<p>CD8(+) cytotoxic T lymphocytes (CTLs) eliminate virally infected cells through directed secretion of specialized lytic granules. Because a single CTL can kill multiple targets, degranulation must be tightly regulated. However, how CTLs regulate the termination of granule secretion remains unclear. Previous work demonstrated that centralized actin reduction at the immune synapse precedes degranulation. Using a combination of live confocal, total internal reflection fluorescence, and superresolution microscopy, we now show that, after granule fusion, actin recovers at the synapse and no further secretion is observed. Depolymerization of actin led to resumed granule secretion, suggesting that recovered actin acts as a barrier preventing sustained degranulation. Furthermore, RAB27a-deficient CTLs, which do not secrete cytotoxic granules, failed to recover actin at the synapse, suggesting that RAB27a-mediated granule secretion is required for actin recovery. Finally, we show that both actin clearance and recovery correlated with synaptic phosphatidylinositol 4,5-bisphosphate (PIP2) and that alterations in PIP2 at the immunological synapse regulate cortical actin in CTLs, providing a potential mechanism through which CTLs control cortical actin density. Our work provides insight into actin-related mechanisms regulating CTL secretion that may facilitate serial killing during immune responses.</p>
},
	issn = {1091-6490},
	doi = {10.1073/pnas.1710751114},
	author = {Ritter, Alex T and Kapnick, Senta M and Murugesan, Sricharan and Schwartzberg, Pamela L and Griffiths, Gillian M and Lippincott-Schwartz, Jennifer}
}
@article {46774,
	title = {Actin depletion initiates events leading to granule secretion at the immunological synapse.},
	journal = {Immunity},
	volume = {42},
	year = {2015},
	month = {2015 May 19},
	pages = {864-76},
	abstract = {<p>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\&nbsp;min, cortical actin reduced across the synapse, T\&nbsp;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\&nbsp;min and reached the synapse after 6\&nbsp;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.</p>
},
	issn = {1097-4180},
	doi = {10.1016/j.immuni.2015.04.013},
	author = {Ritter, Alex T and Asano, Yukako and Stinchcombe, Jane C and Dieckmann, N M G and Chen, Bi-Chang and Gawden-Bone, C and van Engelenburg, Schuyler and Legant, Wesley and Gao, Liang and Davidson, Michael W and Betzig, Eric and Lippincott-Schwartz, Jennifer and Griffiths, Gillian M}
}
