Human cytomegalovirus-specific cytotoxic T cells: their precursor frequency and stage specificity

Abstract

Human virus-specific cytotoxic T (Tc) cells may be important in maintaining the virus/host equilibrium during persistent herpes virus infections such as that with human cytomegalovirus (HCMV). We have previously shown that HCMV-specific Tc cells are present in peripheral blood in normal asymptomatic seropositive individuals (L. K. Borysiewicz et al., Eur. J. Immunol. 1983. 13: 804). In this study we have used limiting dilution analysis to estimate the precursor frequency of these Tc cells and to further delineate their specificity for viral proteins expressed at different stages of the virus replicative cycle. HCMV-specific Tc precursor cells were present in peripheral blood lymphocytes (PBL) at a frequency of 1/5000 to 20,000 E+ PBL. This frequency was higher than that observed for varicella-zoster virus (VZV)-specific Tc cells (1/30,000 to greater than 500,000) in asymptomatic individuals and was similar to the VZV Tc precursor cell frequencies observed following clinical reactivation (1/30,000). When the stage specificity of clonally derived HCMV-specific Tc cells was analyzed, using target cells treated with phosphonoformate to allow expression of only the nonstructural viral proteins, the majority (60%) of Tc cells lysed these cells. A number of Tc cells lysed only cells which expressed the structural or late HCMV proteins. These results suggest a high precursor frequency of HCMV-specific Tc cells in PBL, and that there are subpopulations of such Tc cells specific for HCMV antigens expressed at different stages of the virus replicative cycle. However, the relative frequencies of these subpopulations suggest that the immunodominant HCMV antigens with respect to the Tc response are expressed at immediate early and/or early times.

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

“…In contrast, patients with compromised immune system are susceptible to severe HCMV disease following either primary or recurrent infection [1,2]. Studies of the immune reconstitution in immunocompromised patients pointed to the importance of both CD4 + T helper cells and CD8 + CTL for the control of HCMV infection [3,4].…”

CMV-Specific TCR-Transgenic T Cells for Immunotherapy

“…In these studies, the transferred T cells had been isolated from CMVpositive HSCT donors. With CMV-seronegative donors, isolation and enrichment of CMV-specific T cells are difficult, if not impossible, because naive CMV-specific T cells are too rare to be detected or directly accessed (11,12). As a consequence, CMVseropositive recipients of stem cell grafts from CMV-negative donors are at particular risk to develop severe CMV-related disease because CMV-specific T cell reconstitution is highly deficient (5,13).…”

Ex vivo stimulation of cytomegalovirus (CMV)‐specific T cells using CMV pp65‐modified dendritic cells as stimulators

“…In healthy carriers, the virus lays dormant and is effectively suppressed by CMV-specific T cells (Borysiewicz et al, 1988). In immunosuppressed individuals, such as patients undergoing allogeneic stem cell transplantation, CMV infections are common and may become life threatening (Meyers et al, 1986;Winston et al, 1993;Boeckh et al, 1999;Einsele et al, 2000).…”