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*
Gladstone Institute of Virology and Immunology, and
Departments of Medicine and Microbiology and Immunology, University of California, San Francisco, CA 94141
We investigated the expression and function of Fas on human
thymocytes prepared from fetal and pediatric tissue specimens and from
SCID-hu Thy/Liv grafts. Unlike mouse thymocytes, human thymocytes
exhibited a pattern of Fas expression skewed to immature cells, in that
the highest expression was seen on double negative thymocytes and on
intrathymic T progenitor cells. Fas expression was intermediate on
double positive human thymocytes, and low or negative on mature single
positive CD4 and CD8 medullary thymocytes. In spite of this relatively
abundant surface expression, cross-linking of Fas with agonist mAb was
incapable of triggering an apoptotic signal in human thymocytes.
Apoptotic signaling was not enhanced by treatment with cycloheximide,
nor by restoring a cosignaling milieu by addition of thymic stromal
cells. Mouse thymocytes were induced to apoptosis by cross-linked
recombinant soluble human Fas ligand both in vitro and in vivo, though
human thymocytes were also resistant to this mode of receptor ligation.
Membrane-bound Fas ligand also induced apoptotic death in murine
thymocytes but not in human thymocytes. Human thymocytes were as
sensitive as Jurkat cells, however, to apoptosis induced by TNF-
,
suggesting that these cells have a signaling defect before activation
of the earliest caspases. These data demonstrate a durable and specific
resistance of human thymocytes to apoptosis induced through Fas
receptor engagement, and reveal significant species-specific
differences in the biology of thymocyte-programmed cell
death.
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