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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3084-3093
Viral-Specific Cytotoxic T Lymphocytes Lyse Human Immunodeficiency
Virus-Infected Primary T Lymphocytes by the Granule Exocytosis Pathway
Premlata Shankar,
Zhan Xu, and
Judy Lieberman
From The Center for Blood Research, Harvard Medical School, Boston,
MA.
Cytotoxic T lymphocytes (CTL) lyse antigen-bearing target cells by
two distinct pathways. Whereas granule exocytosis targets any
antigen-bearing cell, fas-mediated cytotoxicity kills only fas-expressing cells and does not require antigen expression. Fas
pathway activation can potentially lead to lysis of uninfected bystander cells. We examined the relative usage of the two pathways by
CTL clones and cell lines directed against four different human immunodeficiency virus (HIV) proteins in lysing primary HIV-infected targets. Although fas was expressed on HIV-infected primary
CD4+ T cells, their lysis by antigen-specific
CD8+ CTL was only by the granule pathway. Fas ligand
(fasL) was not detectable on antigen-specific CD8 clones, T-cell lines,
or circulating HIV-specific CD8 T cells from HIV-infected donors,
stained with a tetrameric HLA-A2-HIV-peptide complex. FasL expression
by HIV-specific CTL clones was not activated by exposure to
HIV-presenting cells, but was after unphysiological stimulation with
phorbol myristate acetate (PMA). CTL clones did not lyse
bystander Jurkat cells, but HIV-infected primary CD4+ T
cells lysed uninfected bystander cells by the fas-mediated pathway.
These results suggest that HIV-specific CD8+ CTL do not
cause HIV immunopathology by lysing bystander cells. On the contrary,
fas-mediated lysis of uninfected cells by HIV-infected cells may
contribute to CD4 decline.
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