Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection

To obtain insight into human CD4(+) T cell differentiation and selection in vivo, we longitudinally studied cytomegalovirus (CMV)-specific CD4+ T cells after primary infection. Early in infection, CMV-specific CD4+ T cells have the appearance of interferon gamma (IFN gamma)-producing T-helper 1 (T(H)1) type cells, whereas during latency a large population of CMV-specific CD4(+)CD28(-) T cells emerges with immediate cytotoxic capacity. We demonstrate that CD4(+)CD28(-) T cells could lyse CMV antigen-expressing target cells in a class II-dependent manner. To clarify the clonal relationship between early and late CMV-specific CD4(+) T cells, we determined their V beta usage and CDR3 sequences. The T-cell receptor beta (TCRP) diversity in the early CMV-specific CD4(+) T-cell population was high in contrast to the use of a very restricted set of TCR beta sequences in latent infection. T-cell clones found in the late CMV-specific CD4(+) T-cell population could not be retrieved from the early CD4(+) T-cell population, or were present only at a low frequency. The observation that dominant CMV-specific CD4(+) clones during latency were only poorly represented in the acute phase suggests that after the initial control of the virus strong selection and/or priming of novel clones takes place in persistent infections in humans.