DIRECT VISUALIZATION AND QUANTITATION OF CYTOMEGALOVIRUS-SPECIFIC CD8+ CYTOTOXIC T-LYMPHOCYTES IN LIVER TRANSPLANT PATIENTS1

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Abstract
CMV infection remains a significant clinical problem in the context of LT. Changes in the magnitude of the CMV-specific CTL response after LT have not previously been assessed but may be important in determining the outcome of CMV infection. Method. We used a fluorescent HLA-B*0702-CMV peptide tetrameric complex to directly visualize and quantitate CMV-specific CD8+ CTL both in immunosuppressed patients after LT and in immunocompetent controls. CMV-specific CD8+ CTL, at a frequency ranging from 0.1 to 5.8% of CD8+, were detected in the peripheral blood of 22 of 25 B*0702, CMV immunoglobulin G seropositive individuals, with no difference observed between immunocompetent controls and patients >3 years after LT. In CMV seropositive LT recipients who did not have symptomatic CMV infection during the first 3 months after LT, CMV-specific CD8+ CTL magnitude initially decreased, then increased up to 5 times higher than pre-LT levels within 3 months. Two CMV seronegative recipients of seropositive donors had symptomatic CMV infection in association with high viral load. In both patients, no CD8+ CTL response was detected before the onset of symptoms, and a reduction in viral load was observed during antiviral therapy. However, polymerase chain reaction negativity was achieved only when a demonstrable CMV-specific CD8+ CTL response was generated. Responses were never observed in asymptomatic CMV seronegative patients. We suggest that the generation of CMV-specific CD8+ CTL may be driven by, and seems to coincide with the suppression of, viral reactivation. Direct monitoring of CMV-specific CD8+ CTL using an HLA-peptide tetramer may prove to be of value in the management of patients after LT.