The correlates of protective immunity to disease-inducing viruses in humans remain to be elucidated. We determined the kinetics and characteristics of cytomegalovirus (CMV)-specific CD4 ؉ and CD8 ؉ T cells in the course of primary CMV infection in asymptomatic and symptomatic recipients of renal transplants. Specific CD8 ؉ cytotoxic T lymphocyte (CTL) and antibody responses developed regardless of clinical signs. CD45RA ؊ CD27 ؉ CCR7 ؊ CTLs, although classified as immature effector cells in HIV infection, were the predominant CD8 effector population in the acute phase of protective immune reactions to CMV and were functionally competent. Whereas in asymptomatic individuals the CMV-specific CD4 ؉ T-cell response preceded CMV-specific CD8 ؉ T-cell responses, in symptomatic individuals the CMV-specific effectormemory CD4 ؉ T-cell response was delayed and only detectable after antiviral therapy.The appearance of disease symptoms in these patients suggests that functional CD8 ؉ T-cell and antibody responses are insufficient to control viral replication and that formation of effector-memory CD4 ؉ T cells is necessary for recovery of infection.

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Two prototypic types of virus-specific CD8+ T cells can be found in latently infected individuals: CD45R0+CD27+CCR7− effector-memory, and CD45RA+CD27−CCR7− effector-type cells. It has recently been implied that CD45RA+CD27−CCR7− T cells are terminally differentiated effector cells and as such have lost all proliferative capacity. We show in this study, however, that stimulation of CMV-specific CD45RA+CD27−CCR7− T cells with their cognate peptide in concert with either CD4+ help or IL-2, IL-15, or IL-21 in fact induces massive clonal expansion. Concurrently, these stimulated effector T cells change cell surface phenotype from CD45RA to CD45R0 and regain CCR7, while effector functions are maintained. Our data imply that CD45RA+CD27−CCR7− effector-type T cells contribute to immunity not only by direct execution of effector functions, but also by yielding progeny in situations of viral reinfection or reactivation.

Based on the expression of the TNFR SFP CD27, two Ag-primed CD8+ T cell subsets can be discerned in the circulation of healthy individuals: CD27+ T cells that produce a variety of cytokines but do not display immediate cytolytic activity; and cytotoxic CD27− T cells, which secrete only IFN-γ and TNF-α. The mechanism that controls the generation of these different phenotypes is unknown. We show that CMV reactivation not only increases the number of virus-specific T cells but also induces their transition from a CD27+ to a CD27− phenotype. In support of a relation between pool size and phenotype in a cohort of latently infected individuals, the number of Ag-specific CD27− CD8+ T cells was found to be linearly related to the total number of CMV-specific CD8+ T cells. In vitro studies revealed that the acquisition of the CD27− phenotype on CMV-specific T cells depended on the interaction of CD27 with its cellular ligand, CD70. Expression of CD70 was proportional to the amount of antigenic stimulation and blocked by the CD4+ T cell-derived cytokine IL-21. Thus, induction of CD70, which may vary in distinct viral infections, appears to be a key factor in determining the size and phenotype of the CMV-specific T cell population in latently infected individuals.

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In patients with B-cell chronic lymphocytic leukemia (B-CLL), the absolute number of T cells is increased. Although it has been suggested that these T cells might be tumor specific, concrete evidence for this hypothesis is lacking. We performed a detailed immunophenotypic analysis of the T-cell compartment in the peripheral blood of 28 patients with B-CLL (Rai 0, n ‫؍‬ 12; Rai I-II, n ‫؍‬ 10; Rai III-IV, n ‫؍‬ 6) and 12 healthy age-matched controls and measured the ability of these patients to mount specific immune responses. In all Rai stages a significant increase in the absolute numbers of CD3 ؉ cells was observed. Whereas the number of CD4 ؉ cells was not different from controls, patients with B-CLL showed significantly increased relative and absolute numbers of CD8 ؉ cells, which exhibited a CD45RA ؉ CD27 ؊ cytotoxic phenotype. Analysis of specific immune responses with tetrameric cytomegalovirus (CMV)-peptide complexes showed that patients with B-CLL had significantly increased numbers of tetramerbinding CMV-specific CD8 ؉ T cells. The rise in the total number of CD8 ؉ cytotoxic T cells was evident only in CMV-seropositive B-CLL patients. Thus, our data suggest that in patients with B-CLL the composition of T cells is shifted toward a CD8 ؉ cytotoxic cell type in an effort to control infections with persistent viruses such as CMV. Moreover, they offer an explanation for the high incidence of CMV reactivation in CLL patients treated with T cell-depleting agents, such as the monoclonal antibody (mAb) alemtuzumab (Campath; ␣-CD52 mAb). Furthermore, because in CMV-seronegative patients no increase in cytotoxic CD8 ؉ T cells is found, our studies do not support the hypothesis that tumor-specific T cells account for T-cell expansion in B-CLL.