Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 102

ability of donor CD8 + T cells to prevent rejection. In contrast, approximately
2 or 3 × 10 6 perforin-deficient T cells were needed to prevent rejection in
50% of the recipients, demonstrating that under these conditions, perforin-
deficient T cells had approximately 3-5% of wild-type activity in preventing
marrow graft rejection. With as many as 1 or 2 × 10 7 doubly mutant donor
CD8 + T cells deficient in both Fas ligand binding and perforin expression
added to the graft, all recipients rejected the graft, demonstrating that the
doubly mutant T cells had less than 1% of wild-type activity in preventing
marrow graft rejection.

Donor CD8 T cells deficient in expression of perforin, Fas ligand binding
or both perforin and Fas ligand binding can influence engraftment pro-
cesses early after HCT under conditions where rejection is mediated by
radiation sensitive recipient T cells [114] . Perforin-deficient donor CD8 T
cells paradoxically were able to support spleen colony formation by donor
marrow cells on day 5 after HCT in sublethally irradiated allogeneic recipi-
ents but were not able to prevent long-term rejection. Controls showed
no spleen colony formation or long-term engraftment when marrow was
given in the absence of donor T cells, whereas wild-type T cells were able
to support spleen colony formation and prevented long-term rejection.
Earlier studies showed that recipient T cells do not reject allogeneic hema-
topoietic stem cells until at least 5 days after HCT [23] . Taken together,
the results demonstrate that in certain strain combinations: (i) donor
T cells are required to support migration of donor hematopoietic cells into
the recipient spleen during the first week after HCT; and (ii) this effect does
not depend on the cytotoxic function of the donor T cells.

104

Taken together, these results elucidated the most potent biological mecha-
nism that accounts for the ability of donor T cells to prevent marrow graft
rejection: cytotoxic donor CD8 + T cells recognize antigens expressed by
recipient T cells that could cause rejection and eliminate these cells through
a perforin-dependent mechanism. In the canine model, donor CD4 + and
CD8 + T cells had equivalent ability to prevent marrow graft rejection [115] .
These observations are consistent with results showing that both resting
and activated canine T cells express MHC-class II antigens. In humans,
however, depletion of donor CD8 + T cells from the graft was associated
with an increased risk of graft rejection in HLA-identical recipients. These
results indicated that donor CD4 + cells are not sufficient to prevent rejec-
tion in humans, even though activated human T cells express HLA-class II
molecules.

In vitro -stimulated T cells can be functionally polarized as type-1 effector
cells that preferentially produce interferon-γ and IL-2 or as type-2 effector
cells that preferentially produce IL-4, IL-5 and IL-10 (see chapter 11). In a
P1 → P2 strain combination that permits recognition of recipient alloanti-
gens by the donor, as well as recognition of donor alloantigens by the recipi-
ent, 1.0 × 10 6 non-polarized donor T cells prevented marrow graft rejection
in mice reconstituted with 1.0 × 10 4 recipient T cells after lethal TBI, but 9
of the 10 recipients died with GVHD [116] . With 1.0 × 10 7 type-2 polarized
T cells added to the graft, 7 of 10 recipients survived without rejection or
lethal GVHD, but with 2.5 × 10 7 type-2 polarized T cells added to the graft,
all recipients died, presumably with GVHD.