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Characterization of the Fas Ligand/Fas-Dependent Apoptosis of Antiretroviral, Class I MHC Tetramer-Defined, CD8⁺ CTL by In Vivo Retrovirus-Infected Cells¹

Department of Microbiology and Immunology and The Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756

C57BL/6 (B6; H-2^b) mice mount strong AKR/Gross murine leukemia virus (MuLV)-specific CD8⁺ CTL responses to the immunodominant K^b-restricted epitope, KSPWFTTL, of endogenous AKR/Gross MuLV. In sharp contrast, spontaneous virus-expressing AKR.H-2^b congenic mice are low/nonresponders for the generation of AKR/Gross MuLV-specific CTL. Furthermore, when viable AKR.H-2^b spleen cells are cocultured with primed responder B6 antiviral precursor CTL, the AKR.H-2^b cells function as "veto" cells that actively mediate the inhibition of antiviral CTL generation. AKR.H-2^b veto cell inhibition is virus specific, MHC restricted, contact dependent, and mediated through veto cell Fas ligand/responder T cell Fas interactions. In this study, following specific priming and secondary in vitro restimulation, antiretroviral CD8⁺ CTL were identified by a labeled K^b/KSPWFTTL tetramer and flow cytometry, enabling direct visualization of AKR.H-2^b veto cell-mediated depletion of these CTL. A 65–93% reduction in the number of B6 K^b/KSPWFTTL tetramer⁺ CTL correlated with a similar reduction in antiviral CTL cytotoxicity. Addition on sequential days to the antiviral CTL restimulation cultures of either 1) AKR.H-2^b veto cells or 2) a blocking Fas-Ig fusion protein (to cultures also containing AKR.H-2^b veto cells) to block inhibition demonstrated that AKR.H-2^b veto cells begin to inhibit B6 precursor CTL/CTL expansion during days 2 and 3 of the 6-day culture. Shortly thereafter, a high percentage of B6 tetramer⁺ CTL cocultured with AKR.H-2^b veto cells was annexin V positive and Fas^high, indicating apoptosis as the mechanism of veto cell inhibition. Experiments using the irreversible inhibitor emetine demonstrated that AKR.H-2^b cells had to be metabolically active and capable of protein synthesis to function as veto cells. Of the tetramer-positive CTL that survived veto cell-mediated apoptosis, there was no marked skewing from the preferential usage of V4, 8.1/8.2, and 11 TCR normally observed. These findings provide further insight into the complexity of host/virus interactions and suggest a fail-safe escape mechanism by virus-infected cells for epitopes residing in critical areas of viral proteins that cannot accommodate variations of amino acid sequence.

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