HLA-restricted cytotoxic T lymphocyte and nonthymic cytotoxic lymphocyte responses to cytomegalovirus infection of bone marrow transplant recipients

Fifteen bone marrow transplant recipients were studied prospectively to define cell-mediated immune responses to cytomegalovirus (CMV) infection. Assays included measurements of lymphocyte cytotoxic activities and blastogenesis in response to viral antigens and concanavalin A (Con A). Cytotoxicity assays included measurement of natural killer (NK) cell activity using the K562 cell line, antibody-dependent killer (K) cell activity using alloantibody sensitized Chang cells, and antiviral cytotoxicity using HLA-typed, cryopreserved infected and uninfected skin fibroblasts as target cells. During the period of study, 8 patients developed disseminated CMV infection, 1 developed disseminated adenovirus type 1 infection, 1 developed pneumocystis carinii pneumonia, and 5 patients did not develop systemic virus infection. CMV interstitial pneumonitis was fatal in 3 patients, who had very low NK cell activity at onset of infection and minimal or no specific cytotoxic lymphocyte responses to infection. Peripheral blood lymphocytes (PBL) from the 5 patients who survived the infection had measurable NK cell activity at onset of infection, significant responsiveness of lymphocytes to Con A, and CMV-specific cytotoxic lymphocyte responses to infection. In 3 patients with primary infection and 1 with secondary infection this cytotoxicity was mediated by both HLA-restricted cytotoxic T cells and nonthymic lymphocytes; erythrocyte rosetting cells were HLA-restricted whereas nonrosetting cells were not. In the other patient who had secondary infection the cytotoxicity was mediated only by lymphocytes that were not HLA-restricted. The responses appeared to be specifically induced by CMV infection, because they were not observed in uninfected patients or in patients with other types of systemic infection. The findings indicate that HLA-restricted cytotoxic T lymphocytes develop in vivo and that this and other types of cytotoxic lymphocyte activity are involved in the immune response to human CMV infection.