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Fig. 21.7 Lytic granules are on the move. CTLs were settled onto planar lipid bilayers
containing the adhesion protein ICAM-1 (blue) and cognate peptide-MHC ligands (unstained)
recognizable by the CTL-TcR. Secretory vesicle contents are shown in red. a Strong TcR
signaling causes vesicles (red) concentrate at around the MTOC prior to MTOC translocation
resulting in their clustering at the center of the immunological synapse (cSMAC). b Weaker or
indolent TcR signaling leads to MTOC translocation prior to clustering of secretory vesicles
around the MTOC. Here vesicles traveling from the periphery toward the MTOC still arrive at the
synapse but tend to get stuck in the pSMAC. The central location of vesicles is associated with
more rapid granule release and faster destruction of target cells
These considerations led us to propose a model in which variations in the
kinetics of early TCR signaling could determine the difference in temporal and
spatial coordination of the two principal movements (Sykulev 2010 ). If the
kinetics of Ca 2+ signaling is rapid, the granules are recruited to MTOC prior to
the MTOC polarization, and subsequent MTOC polarization directly delivers the
granules to the secretory domain (Fig. 21.7 a). The granule delivery via this short
path is associated with rapid kinetics of target cell destruction by CTL. Slow
kinetics of Ca 2+ signaling allows the MTOC to polarize before the granules reach
the MTOC, and the granules are redirected to the periphery of the synaptic
interface (Fig. 21.7 b). The granules then have to travel across the adhesion ring to
be released at the center of the synaptic interface which is devoid of polymerized
F-actin—the long path. The long path of granule delivery is linked to inefficient,
i.e., slow, target cell destruction by CTL.
During the interaction of T cells and targets, formation of the immunological
synapse is associated with polymerization of actin and a transient formation of an
actin ring. Studies by Beal and colleagues indicate that the stability of this actin
ring is related to sensitivity of the target cell to lysis by CTL (Beal et al. 2008 ).
There are several possible explanations for this observation. One possibility is that
actin is directly involved in driving MTOC translocation as mentioned above
(Stinchcombe et al. 2006 ). Alternatively, it might be associated with recruitment of
ADAP which interacts with actin through its Ena/VASP binding domain and has
also been implicated in the recruitment of dynein (Combs et al. 2006 ; Obergfell
et al. 2001 ). Finally, this actin ring might be associated with forming a seal that
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