Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 105

reconstituted with small numbers of recipient T cells before HCT [125] . The
ability of F1 CD8 T cells to prevent rejection of parental marrow is difficult
to explain solely through a veto mechanism, because rejection could be
mediated through recognition of either MHC-class I or -class II alloantigens
in the models that were tested. As noted above, a donor veto mechanism
can inhibit responses only against alloantigens expressed by the veto cells
itself. Murine T cells cannot veto MHC-class II responses, since they do not
express MHC-class II alloantigens. One possible explanation of this paradox
is that activated veto cells might recruit or activate NK cells derived from the
F1 graft to help eliminate parental recipient T cells that survive the condi-
tioning regimen.

Since F1 T cells cannot be generated in humans, other avenues have been
explored to translate the use of veto cells to prevent graft rejection after HCT
in humans. One such approach involves the development of donor-derived
cytotoxic T-cell lines that recognize third-party alloantigens but not recipi-
ent alloantigens. Effector cytotoxic cell lines generated against third-party
alloantigens by in vitro stimulation and culture can prevent graft rejection
without causing GVHD both in naïve recipients and in recipients presensi-
tized against donor cells [126] . The activity of these cells was enhanced by
treatment of the recipients with sirolimus after HCT.

107

Subsequent studies showed that cytotoxic T-cell lines with a central
memory phenotype prevented rejection more efficiently than conven-
tional cytotoxic T-cell lines with an effector phenotype or an effector
memory phenotype [127] . T cells with a central memory phenotype home
preferentially to lymph nodes and have longer survival in vivo compared
to effector cells or effector memory cells. These characteristics of central
memory T cells could explain their enhanced ability to prevent rejection
compared to other types of T cells. Again, however, a pure veto mecha-
nism cannot explain how third-party-specific donor T cells could prevent
rejection entirely through veto activity in a model where rejection can be
mediated by recipient cells that recognize donor MHC-class II alloanti-
gens. As in the experiments that used F1 donor cells and parental recipi-
ents, it is possible that donor NK cells helped to prevent rejection in these
models.

A variety of experiments have indicated that veto-mediated inactivation
of cytotoxic effector T cells occurs through induction of apoptosis, but
studies exploring the molecular mechanisms leading to apoptosis have
yielded distinctly different conclusions. The original studies indicated
that apoptosis of cytotoxic effector T cells is induced through a mecha-
nism involving two simultaneous signal transduction mechanisms, the
first delivered through the T-cell receptor of the cytotoxic effector when it
recognizes an antigen expressed by the veto cells, and the second deliv-
ered when the α3 domain of MHC-class I molecules on the cytotoxic effec-
tor cell interacts with CD8 molecules on the target veto cells [128,129]
( Figure 5.2 ). More recent studies have indicated that apoptosis of cytotoxic
effector cells is induced through a mechanism in which the target veto
cells actively participate in the process [130] . According to this model, the
target veto cells are activated through a Ca 2+ and lck-dependent process
that leads to Src kinase activation and Erk phosphorylation, followed by