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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1047-1055
Differential use of FasL- and perforin-mediated
cytolytic mechanisms by T-cell subsets involved in graft-versus-myeloid
leukemia responses
Michael H. Hsieh and
Robert Korngold
From the Kimmel Cancer Institute, Jefferson Medical College,
Philadelphia, Pennsylvania.
In graft-versus-leukemia (GVL) responses, the cellular subsets and
effector mechanisms responsible for cytotoxicity against leukemic cells
in vivo remain poorly characterized. A murine model of
syngeneic GVL that features CD4+ and CD8+
T-cell responses against the MMB3.19 myeloid leukemia cell line has
been previously described. MMB3.19 expresses high levels of functional
Fas and tumor necrosis factor (TNF) receptors that do not transduce
proapoptotic signals. Through the use of perforin- and Fas ligand
(FasL)-deficient mice, it was demonstrated that CD4+ T
cells mediate anti-MMB3.19 effects in vivo primarily through the use of
FasL and secondarily through perforin mechanisms. Conversely, CD8+ T cells induce GVL effects primarily through the use
of perforin and minimally through FasL mechanisms. Although the in vivo
observations of CD8+ T cells were reflective of their in
vitro cytotoxic T lymphocyte (CTL) activity, for CD4+ T
cells, in vitro responses were dominated by the perforin pathway. In
addition, the diminished capacity of T cells from perforin- and
FasL-deficient mice to lyse MMB3.19 target cells appeared directly
related to their deficient cytotoxic functions rather than to defects
in activation because these cells were fully capable of mounting
proliferative responses to the tumor cells. These findings demonstrate
that GVL responses of T-cell subsets can involve preferential use of
different cytotoxic mechanisms. In particular, these
findings identify a role for both FasL-employing CD4+
CTLs and the more novel perforin-utilizing CD4+ T-cell
subset in responses against a myeloid leukemia.
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