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Blood, 15 May 2001, Vol. 97, No. 10, pp. 2923-2931
PLENARY PAPER
Expansion of cytolytic CD8+ natural killer T cells
with limited capacity for graft-versus-host disease induction due to
interferon  production
Jeanette Baker,
Michael R. Verneris,
Maki Ito,
Judith A. Shizuru, and
Robert
S. Negrin
From the Department of Medicine, Division of Bone
Marrow Transplantation, Stanford University Medical Center, Stanford,
CA.
T cells with natural killer cell phenotype and function (NKT cells)
have been described in both human and murine tissues. In this study,
culture conditions were developed that resulted in the expansion of
CD8+ NKT cells from bone marrow, thymus, and spleen by the
timed addition of interferon- (IFN-), interleukin 2 (IL-2), and
anti-CD3 monoclonal antibody. After 14 to 21 days in culture, dramatic
expansion of CD3+, CD8+,   T-cell
receptor+ T cells resulted with approximately 20% to 50%
of the cells also expressing the NK markers NK1.1 and DX5. The
CD8+ NKT cells demonstrated lytic activity against several
tumor target cells with more than 90% lysis by day 14 to day 21 of
culture. Cytotoxicity was observed against both syngeneic and
allogeneic tumor cell targets with the greatest lytic activity by the
cells expressing either NK1.1 or DX5. The expanded CD8+ NKT
cells produce TH1-type cytokines with high levels of
IFN- and tumor necrosis factor . Expansion of the
CD8+ NKT cells was independent of CD1d. Ly49 molecules were
expressed on only a minority of cells. A single injection of expanded
CD8+ NKT cells was capable of protecting syngeneic animals
from an otherwise lethal dose of Bcl1 leukemia cells. Expanded
CD8+ NKT cells produced far less graft-versus-host disease
(GVHD) than splenocytes across major histocompatibility barriers, even when 10 times the number of CD8+ NKT cells as compared to
splenocytes were injected. This reduction in GVHD was related to
IFN- production since cells expanded from IFN- knock-out animals
caused acute lethal GVHD, whereas cells expanded from animals defective
in fas ligand, fas, IL-2, and perforin did not. These data
indicate that CD8+ NKT cells expanded in this fashion could
be useful for preserving graft-versus-leukemia activity without causing GVHD.
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