Submitted March 2, 2006
Accepted June 26, 2006
Strong selection of virus-specific cytotoxic CD4+ T cell clones during primary human cytomegalovirus infection
Ester M van Leeuwen*, Ester B Remmerswaal, Mirjam H Heemskerk, Ineke J ten Berge, and Rene A van Lier
Department of Experimental Immunology, Dept. of Internal Medicine,Academic Medical Center, Amsterdam
Dept. of Hematology, Leiden University Medical Center, Leiden, The Netherlands
Department of Internal Medicine, Division of Nephrology, Academic Medical Center, Amsterdam
Department of Experimental Immunology, Academic Medical Center, Amsterdam
* Corresponding author; email: e.m.vanleeuwen{at}amc.uva.nl.
To obtain insight in 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 IFN
-producing TH1 type cells, whereas during latency a large population of CMV-specific CD4+CD28- T cells emerges with immediate cytotoxic capacity. We here 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
usage and CDR3 sequences. The TCR diversity in the early CMV-specific CD4+ T cell population was high in contrast to the use of a very restricted set of TCR sequences in latent infection. T-cell clones found in the late CMV-specific CD4+ T cell population could not, or only at low frequency, be retrieved from the early CD4+ T cell population. 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 man.
