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 (IFNgamma)-producing T-helper 1 (TH1) 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 Vbeta usage and CDR3 sequences. The T-cell receptor beta (TCRbeta) diversity in the early CMV-specific CD4+ T-cell population was high in contrast to the use of a very restricted set of TCRbeta 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.
van Leeuwen
Ester M M
EM
Department of Experimental Immunology, Division of Nephrology, Academic Medical Center, Amsterdam, the Netherlands.
Remmerswaal
Ester B M
EB
Heemskerk
Mirjam H M
MH
ten Berge
Ineke J M
IJ
van Lier
Rene A W
RA
D000595:Amino Acid Sequence; D000918:Antibody Specificity; D016207:Cytokines / Q000032:analysis; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D006681:HLA-D Antigens / Q000276:immunology; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016207:Cytokines; D006681:HLA-D Antigens; D010446:Peptide Fragments