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*
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, MD 20814
CD8+ T lymphocytes that specifically recognize tumor
cells can be isolated and expanded ex vivo. While the lytic properties
of these cells have been well described, their fate upon encounter with
cognate tumor is not known. We performed reverse 51Cr
release assays in which the lymphocyte effectors rather than the tumor
cell targets were radioactively labeled. We found that melanoma tumor
cells caused the apoptotic death of tumor-specific T cells only upon
specific MHC class I-restricted recognition. This death was entirely
blockable by the addition of an Ab directed against the Fas death
receptor (APO-1, CD95). Contrary to the prevailing view that
tumor cells cause the death of anti-tumor T cells by expressing Fas
ligand (FasL), our data suggested that FasL was instead expressed by T
lymphocytes upon activation. While the tumor cells did not express FasL
by any measure (including RT-PCR), functional FasL (as well as FasL
mRNA) was consistently found on activated anti-tumor T cells. We
could successfully block the activation-induced cell death with
z-VAD-fmk, a tripeptide inhibitor of IL-1ß-converting enzyme
homologues, or with anti-Fas mAbs. Most importantly, these
interventions did not inhibit T cell recognition as measured by IFN-
release, nor did they adversely affect the specific lysis of tumor cell
targets. These results imply that Fas-mediated activation-induced cell
death could be a limiting factor in the in vivo efficacy of adoptive
transfer of class I-restricted CD8+ T cells and provide a
means of potentially enhancing their growth in vitro as well as their
function in vivo.
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