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*
Ludwig Institute for Cancer Research, Lausanne Branch, and
Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland
This study describes a form of partial agonism for a
CD8+CTL clone, S15, in which perforin-dependent killing and
IFN-
production were lost but Fas (APO1 or CD95)-dependent
cytotoxicity preserved. Cloned S15 CTL are H-2Kd restricted
and specific for a photoreactive derivative of the Plasmodium
berghei circumsporozoite peptide PbCS 252–260 (SYIPSAEKI). The
presence of a photoactivatable group in the epitope permitted
assessment of TCR-ligand binding by TCR photoaffinity labeling.
Selective activation of Fas-dependent killing was observed for a
peptide-derivative variant containing a modified photoreactive group. A
similar functional response was obtained after binding of the wild-type
peptide derivative upon blocking of CD8 participation in TCR-ligand
binding. The epitope modification or blocking of CD8 resulted in an
8-fold decrease in TCR-ligand binding. In both cases, phosphorylation
of 
-chain and ZAP-70, as well as calcium mobilization were reduced
close to background levels, indicating that activation of Fas-dependent
cytotoxicity required weaker TCR signaling than activation of
perforin-dependent killing or IFN- production. Consistent with this,
we observed that depletion of the protein tyrosine kinase
p56lck by preincubation of S15 CTL with
herbimycin A severely impaired perforin- but not Fas-dependent
cytotoxicity. Together with the observation that S15 CTL constitutively
express Fas ligand, these results indicate that TCR signaling too weak
to elicit perforin-dependent cytotoxicity or cytokine production can
induce Fas-dependent cytotoxicity, possibly by translocation of
preformed Fas ligand to the cell surface.
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