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Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2352-2355
Granule exocytosis, and not the Fas/Fas ligand system, is the main
pathway of cytotoxicity mediated by alloantigen-specific
CD4+ as well as CD8+ cytotoxic T lymphocytes
in humans
Masaki Yasukawa,
Hideki Ohminami,
Junko Arai,
Yoshihito Kasahara,
Yasushi Ishida, and
Shigeru Fujita
From the First Department of Internal Medicine, Ehime University
School of Medicine, Shigenobu, Ehime; Department of Pediatrics,
Kanazawa University School of Medicine, Kanazawa, Ishikawa; and
Department of Pediatrics, Ehime Prefectural Central Hospital,
Matsuyama, Ehime, Japan.
We investigated the cytotoxicity mechanisms of alloantigen-specific
human CD4+ and CD8+ cytotoxic T lymphocytes
(CTLs) using cells from family members with the Fas gene mutation.
Alloantigen-specific CD4+ and CD8+ CTL bulk
lines and clones were generated from 2 individuals by stimulation of
their peripheral blood lymphocytes with allogeneic Fas / or Fas+/ cell lines that were
established from B-lymphocytes of a patient with Fas deficiency and her
mother, respectively. Both CD4+ and CD8+
CTL bulk lines and clones directed against allogeneic HLA antigens exerted cytotoxicity against Fas/ and
Fas+/ cells to almost the same degree. The
cytotoxicity of CD4+ and CD8+ CTLs appeared
to be Ca2+-dependent and was completely inhibited by
concanamycin A, an inhibitor of perforin-mediated cytotoxicity.
Messenger RNAs for the major mediators of CTL cytotoxicity, Fas ligand,
perforin, and granzyme B were all detected in these CD4+
CTLs with the use of the reverse transcriptase polymerase chain reaction. The majority of CD4+ CTL clones that showed
Fas-independent cytotoxicity were TH0, as determined by
their cytokine production profile. These data, obtained with the use of
a novel experimental system, clearly show that the main pathway of
cytotoxicity mediated by alloantigen-specific human CD4+
as well as by CD8+ CTLs is granule exocytosis, and not
the Fas/Fas ligand system.
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