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Differential Sensitivity of CD4+ and CD8+
T Lymphocytes to the Killing Efficacy of Fas (Apo-1/CD95)
Ligand+ Tumor Cells in B Chronic Lymphocytic Leukemia
Inge Tinhofer,
Ingrid Marschitz,
Marion Kos,
Traudl Henn,
Alexander Egle,
Andreas Villunger, and
Richard Greil
From the Laboratory of Molecular Cytology, Department of Internal
Medicine, University of Innsbruck, Innsbruck, Austria.
B-chronic lymphocytic leukemia (B-CLL) is characterized by cellular
and humoral immune defects resulting in increased rates of infection
and disturbed immune surveillance against cancer cells as well as by
the expansion of slowly proliferating tumor cells. We found increased
Fas receptor (FasR) expression in peripheral blood CD4+
and CD8+ cells of B-CLL patients compared with the
equivalent cells of healthy donors. Although increased Fas receptor
expression was significant in both T-lymphocytic subsets, only
CD4+ cells from B-CLL patients underwent apoptosis after
treatment with the agonistic Fas antibody CH11. In CD4+
cells of B-CLL patients, the Fas-sensitivity also correlated with a
CD4+/CD8+ ratio below the lower threshold
of healthy individuals (<1.0). By contrast, FasR expression in the
CD19+ fraction of B-CLL patients was downregulated
compared with normal controls, and this was associated with an
insensitivity to CH11-induced apoptosis. The B-CLL cell line EHEB as
well as CD19+ cells from B-CLL patients constitutively
expressed Fas ligand (FasL). The FasL was functionally active, as the
B-CLL cell line as well as T-cell-depleted CD19+ B-CLL
fractions were able to kill target T-acute lymphatic leukemia (T-ALL)
cells in vitro. This effect was inhibited by the antagonistic FasR-antibody ZB4, the neutralizing anti-FasL monoclonal antibody (MoAb) NOK-2 or by transfection of the caspase inhibitor crmA. These
data point to the fact that expression of FasL on CD19+
B-CLL cells, together with enhanced susceptibility of
CD4+ T cells toward FasL-bearing effector cells, are
causally linked to the relative reduction of CD4+ cells
occurring during B-CLL progression. These findings could explain the
inversion of the ratio of CD4+/CD8+ cell
numbers, which may be causally linked to the immune deficiency observed
in these patients and to the expansion of the neoplastic clone in
B-CLL.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4273-4281
© 1998 by The American Society of Hematology.
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