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Minor histocompatibility antigens HA-1-, -2-, and -4-, and HY-specific
cytotoxic T-cell clones inhibit human hematopoietic progenitor cell growth
by a mechanism that is dependent on direct cell-cell contact
WA Marijt, WF Veenhof, E Goulmy, R Willemze, JJ van Rood and JH Falkenburg
Department of Hematology, University Medical Center, Leiden, The
Netherlands.
HLA-identical bone marrow transplantation (BMT) may be complicated by
graft-versus-host disease or graft rejection. Both complications are
thought to be initiated by recognition of minor histocompatibility (mH)
antigens by HLA-restricted mH-antigen-specific T lymphocytes. Using HLA-
A2-restricted mH antigens HA-1-, -2-, and -4-, and HY-specific cytotoxic T
lymphocyte (CTL) clones, we studied the recognition by these CTL clones of
interleukin-2 (IL-2)-stimulated T cells (IL-2 blasts), BM mononuclear cells
(BMMNCs), and hematopoietic progenitor cells (HPCs). We showed that, when
IL-2 blasts from the BM donors who were investigated were recognized by the
HA-1-, -2-, and -4-, and HY- specific CTL clones, their BMMNCs and HPCs
were recognized as well by these CTL clones, resulting in antigen-specific
growth inhibition of erythrocyte burst-forming units (BFU-E),
colony-forming units- granulocyte (CFU-G), and CFU-macrophage (CFU-M). the
HA-2-specific CTL clone, however, inhibited BFU-E and CFU-G growth from
four donors to a lesser extent than from two other donors. We further
investigated whether inhibitory cytokines released into the culture medium
by the antigen-specific stimulated CTLs or by stimulated BMMNCs were
responsible for suppression of HPC growth or whether this effect was caused
by direct cell-cell contact between CTLs and HPCs. HPC growth inhibition
was only observed after preincubation of BMMNCs and CTLs together for 4
hours before plating the cells in semisolid HPC culture medium. When no
cell-cell contact was permitted before plating, neither antigen-stimulated
CTL nor antigen-nonstimulated CTLs provoked HPC growth inhibition.
Culturing BMMNCs in the presence of supernatants harvested after incubation
of BMMNCs and CTL clones together for 4 or 72 hours did also not result in
HPC growth inhibition. Both suppression of HPC growth and lysis of IL-2
blasts and BMMNCs in the 51Cr-release assay appeared to be dependent on
direct cell-cell contact between target cells and CTLs and were not caused
by the release of inhibitory cytokines into the culture medium by
antigen-specific stimulated CTLs or by stimulated BMMNCs. Our results show
that mH-antigen-specific CTLs can inhibit HPC growth by a direct cytolytic
effect and may therefore be responsible for BM graft rejection after
HLA-identical BMT.
Volume 82,
Issue 12,
pp. 3778-3785,
12/15/1993
Copyright © 1993 by The American Society of Hematology
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