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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 925-935
Fas-Independent and Nonapoptotic Cytotoxicity Mediated by a Human
CD4+ T-Cell Clone Directed Against an Acute Myelogenous
Leukemia-Associated DEK-CAN Fusion Peptide
Hideki Ohminami,
Masaki Yasukawa,
Shin Kaneko,
Yoshihiro Yakushijin,
Yasuhito Abe,
Yoshihito Kasahara,
Yasushi Ishida, and
Shigeru Fujita
From the First Departments of Internal Medicine and Pathology and the
Department of Pediatrics, Ehime University School of Medicine, Ehime,
Japan; and the Department of Pediatrics, Kanazawa University School of
Medicine, Ishikawa, Japan.
The mechanism underlying the cytotoxicity mediated by a human
CD4+ cytotoxic T-lymphocyte (CTL) clone directed against
a peptide derived from the acute myelogenous leukemia-associated fusion protein, DEK-CAN, was investigated. A DEK-CAN fusion peptide-specific CD4+ Th0 CTL clone, designated HO-1, was established from
the peripheral blood lymphocytes of a healthy individual. HO-1 exerted
direct but not "innocent bystander" cytotoxicity within 2 hours.
The cytotoxicity mediated by HO-1 was completely
Ca2+-dependent. Because HO-1 lysed peptide-loaded
Fas-deficient target cells derived from a patient with a homozygous
Fas gene mutation, its cytotoxicity appeared to be mediated by
a Fas-independent pathway. In addition, its cytotoxicity was only
partially inhibited by treatment with concanamycin A and strontium
ions, which are inhibitors of the perforin-based cytotoxic pathway.
Although membrane-bound type of tumor necrosis factor- (TNF-) was
expressed on HO-1, an anti-TNF- antibody had no effect on
HO-1-mediated cytotoxicity. HO-1 expressed mRNA for apoptosis-inducing
mediators, including perforin, granzyme B, Fas ligand, TNF-, and
lymphotoxin; however, no DNA fragmentation was detected in target cells
incubated with HO-1 by
5-[125I]Iodo-2'-deoxyuridine release assay
and agarose gel electrophoresis of DNA. Although it has been suggested
that the Fas/Fas ligand system is the main pathway by which
CD4+ CTL-mediated cytotoxicity is exerted in murine
systems, HO-1 produced peptide-specific and HLA-restricted cytotoxicity
via a Fas-independent and nonapoptotic pathway. The present study thus
describes a novel mechanism of cytotoxicity mediated by
CD4+ CTL.
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