Biology Reference
In-Depth Information
macrophages. However, despite a diversity of roles, much of what T cells do can be
summarized in cellular terms as the directed or focused delivery of effector mole-
cules to another cell. This is achieved minimally by a two-step process that involves
focusing of secretory vesicles around the microtubule-organizing center (MTOC)
and movement of the MTOC up to the site of contact with the target cell. These two
steps can apparently occur in either order but the sequence influences the speed and
magnitude of effector molecule delivery (Poenie
2010
; Sykulev
2010
).
Movement of the MTOC to the target contact site in T cells was first described
by Geiger and colleagues (Geiger et al.
1982
) and extended by a series of studies
from Kupfer et al. (
1983
,
1985
,
1986
), Kupfer and Dennert (
1984
), and Kupfer and
Singer (
1989
). During this time, evidence was accumulating to support the idea
that the directional or localized stimulation of the T cell receptor (TcR) led to
directional secretion of cytokines (Kupfer et al.
1986
; Takayama and Sitkovsky
1987
; Poo et al.
1988
) and directional killing (Kupfer et al.
1985
,
1986
). For
example, disruption of microtubules with nocodazole reversibly blocked killing by
NK cells (Kupfer et al.
1983
). Other treatments that blocked MTOC translocation
such as the nonenzymatic cholera toxin B subunit or heat shock also blocked
killing by CTLs (Sugawara et al.
1993
; Knox et al.
1991
).
The importance of focused secretion might be inferred from the early study of
Trenn and colleagues who artificially stimulated secretion by a combination of a
calcium ionophore (ionomycin) and a PKC activator (PMA or Bryostatins) (Trenn
et al.
1988
). They found that the combination of these two compounds induced
significant secretion of lytic vesicle contents but the effect was to increase lysis of
non-antigenic targets while decreasing the lysis of antigen-specific target cells.
This could be interpreted to mean that non-localized stimuli (PMA and ionomycin)
triggered omnidirectional secretion. This in turn led to reduced specific killing,
where secretory vesicles are normally focused and secreted directly at the target
cell, and increased non-specific killing. A similar effect is seen in gunmetal mice
(Stinchcombe
2001b
).
More recent developments have shown that when a T cell contacts an antigen-
bearing cell, a specialized junction develops which has been dubbed the immu-
nological synapse (Fig.
21.1
) (Dustin et al.
2010
; Monks et al.
1998
; Norcross
1984
). Classically, the synapse is characterized by concentric zones containing
particular groups of molecules known as supramolecular activation clusters or
SMACs (Monks et al.
1998
). The central or cSMAC is characterized by accu-
mulation of signaling molecules such as the TcR, CD28, CD2, and PKC-H.
Surrounding the central SMAC is the peripheral or pSMAC. This region is
characterized by a ring of clustered LFA-1, an integrin. In addition to the pSMAC,
there is a third zone known as the distal SMAC (dSMAC) (Freiberg et al.
2002
)
that contains CD43 and CD45, a phosphatase.
Secretion of CTL lytic vesicles appears to be directed to a zone between the
pSMAC and cSMAC (Stinchcombe et al.
2001a
). The mechanism of delivery clearly
involves translocation of the MTOC up to the immunological synapse (Stinchcombe
et al.
2006
) and dynein-driven movement of secretory vesicles toward the MTOC
(Mentlik et al.
2010
; Poenie et al.
2004
) although late stages of vesicle movement
