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Blood, 1 May 2002, Vol. 99, No. 9, pp. 3302-3309
IMMUNOBIOLOGY
Cytokine production and cytolytic mechanism of CD4+
cytotoxic T lymphocytes in ex vivo expanded therapeutic Epstein-Barr
virus-specific T-cell cultures
Qi Sun,
Robert L. Burton, and
Kenneth G. Lucas
From the Bone Marrow Transplantation Program, School of
Medicine, University of Alabama at Birmingham.
Ex vivo expanded Epstein-Barr virus (EBV)-specific T
cells have been successfully applied clinically for adoptive
immunotherapy. However, the role of CD4+ T cells in the
therapeutic T-cell culture has not been established for the
reconstitution of EBV-specific immunity. We isolated and characterized
CD4+ T-cell lines from the ex vivo T-cell cultures.
Monoclonal line PD-F4 and oligoclonal lines ND-R4 and TD-B4 were
CD3+CD4+CD8 . Cytolytic tests with
targets of mismatched major histocompatibility complex (MHC) and
anti-MHC antibodies confirmed that the cytotoxicity of these
CD4+ cells was restricted by MHC class II. Single cells of
ND-R4 expressed interferon- (IFN-, or interleukin 4 (IL-4), but
rarely coexpressed these 2 cytokines. In contrast, PD-F4 coexpressed
IFN-, IL-2, and IL-4. Kinetic studies with PD-F4 showed that
expression of the 3 cytokines plateaued 5 hours upon stimulation and
was then drastically reduced, with a pattern consistent with
independent modulation and differential off-cycle signal requirements.
The cytotoxicity of these CD4+ cells was largely resistant
to brefeldin A, an inhibitor for cytolytic pathways by Fas-ligand
family molecules. Although sensitive to concanamycin A and
ethyleneglycotetraacetic acid, which inhibit cytotoxicity by granule
exocytosis, the CD4+ cytotoxic T lymphocytes (CTLs) did not
express perforin, suggesting a cytotoxic mechanism independent of
perforin although involving exocytosis. Flow cytometric analysis showed
that the CD4+ CTLs expressed granulysin, a recently
identified cytolytic molecule associated with exocytotic cytolytic
granules. These data suggested that CD4+ T cells in the
therapeutic B-lymphoblastoid cell lines-primed T-cell culture are
diverse in producing TH1 and TH2 cytokines, and
may exert specific cytotoxicity via exocytosis of granulysin.
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