T lymphocytes with cellular maturation

Vol. 203, No. 13, December 25, 2006 2865–2877 www.jem.org/cgi/doi/10.1084/jem.20052246 2865 Human CMV is a β herpes virus that establishes lifelong infection. Endothelial, renal epithelial, and pulmonary tissue as well as myeloid cells all contain latent CMV. Seroprevalence increases with age and reaches 30–70% in developed countries (1). Although serious disease can occur, it is rare. In most immunocompetent individuals, infection is asymptomatic (2). The human immune system dedicates tremendous resources to the control of CMV. In CMV-seropositive healthy subjects >60 yr of age, the total number of CD8+ T cells is twice that in age-matched healthy CMV-seronegative subjects (3). The frequency of CD8+ T cells specifi c for individual CMV-derived peptide epitopes is often >1% of the total peripheral CD8+ T cell pool (4). CMV-specifi c CD4+ T cells are also frequent. It has been estimated that in 11% of healthy CMV-seropositive individuals, between 10 and 40% of the total peripheral CD4+ T cell pool is directed against CMV epitopes (5). Similar results have been reported in HIV-infected patients without apparent CMV disease (6). An exhaustive analysis of all 213 human CMV open reading frames found that a median of 10% of the total peripheral blood memory CD4+ T cells pooled from healthy CMV-seropositive individuals was directed against CMV epitopes (7). From these data, the frequency of CMV-specifi c CD4+ T cells appears to be much greater than required to ensure the production of antibodies and functional CD8+ T cells. The occurrence of CMV disease during immunosuppressive treatments and AIDS demonstrates the importance of cellular immunity in the control of CMV infection. It is clear from many studies that CD8+ T cells play a role in the control of viral replication and may require CD4+ T cell help to achieve eff ective viral control (8–14). However, there is also Acquisition of direct antiviral eff ector functions by CMV-specifi c CD4+ T lymphocytes with cellular maturation