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Donor gamma delta T lymphocytes promote allogeneic engraftment across the
major histocompatibility barrier in mice
WR Drobyski and D Majewski
Department of Medicine, Medical College of Wisconsin, Milwaukee, USA.
T cells that express the alpha beta T-cell receptor are thought to be the
T-cell population primarily responsible for facilitating alloengraftment.
The role of gamma delta + T cells that comprise only a minority of mature T
cells in promoting allogeneic engraftment, however, has not been
extensively studied. The purpose of this study was to determine whether
gamma delta T cells were capable of facilitating alloengraftment in murine
recipients of major histocompatibility complex-mismatched marrow grafts. We
developed a model where engraftment of C57BL/6 x 129/F2(H-2b) marrow in
sublethally irradiated (800 cGy) recipients (AKR/J, H-2k) is dependent on
the presence of mature donor T cells in the marrow graft. In this model,
donor T-cell engraftment was significantly augmented by as few as 1 x 10(5)
alpha beta T cells. The role of gamma delta T cells was then investigated
using transgenic donors (C57BL/6 x 129 background) in which a portion of
the T-cell receptor-beta chain gene was deleted by gene targeting so that
these mice lack alpha beta T cells. Addition of 10 x 10(5) naive gamma
delta T cells to T-cell depleted marrow grafts was required to
significantly increase alloengraftment, although donor T cells averaged
< 50% of total splenic T cells. To determine whether higher doses of
gamma delta T cells would improve donor engraftment and eradicate residual
host T cells, gamma delta T cells were ex vivo expanded with a gamma delta
T-cell-specific mono-clonal antibody and interleukin-2 and then
transplanted into irradiated recipients. Transplantation of > or = 160 x
10(6) activated gamma delta T cells was necessary to consistently and
significantly augment donor cell chimerism and enhance hematopoietic
reconstitution when compared to control mice, but host T cells persisted in
these chimeras. Addition of 2.5 x 10(4) mature alpha beta T cells, which
alone were incapable of facilitating engraftment, to T-cell depleted marrow
grafts containing 160 x 10(6) activated gamma delta T cells resulted in
long-term (> 100 day) complete donor engraftment, indicating that
limiting numbers of alpha beta T cells were required in the marrow graft
for the eradication of residual host T cells. Using serial weight curves
and B- cell reconstitution as end points, clinically significant
graft-versus- host disease was not observed in these chimeras under these
experimental conditions. These data show that, whereas less potent than
alpha beta T cells, gamma delta T cells are able to promote engraftment and
enhance hematopoietic reconstitution in allogeneic marrow transplant
recipients.
Volume 89,
Issue 3,
pp. 1100-1109,
02/01/1997
Copyright © 1997 by The American Society of Hematology
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