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Long-Term Stable Expanded Human CD4⁺ T Cell Clones Specific for Human Cytomegalovirus Are Distributed in Both CD45RA^high and CD45RO^high Populations¹

Department of Medicine, University of Cambridge Clinical School, Cambridge, United Kingdom

T cells play an important role in the control of human CMV (HCMV) infection. Peripheral blood CD4⁺ T cell proliferative responses to the HCMV lower tegument protein pp65 have been detected in most healthy HCMV carriers. To analyze the clonal composition of the CD4⁺ T cell response against HCMV pp65, we characterized three MHC class II-restricted peptide epitopes within pp65 in virus carriers. In limiting dilution analysis, we observed high frequencies of pp65 peptide-specific CD4⁺ T cells, many of which expressed peptide-specific cytotoxicity in addition to IFN- secretion. We analyzed the clonal composition of CD4⁺ T cells specific for defined HCMV peptides by generating multiple independent peptide-specific CD4⁺ clones and sequencing the TCR -chain. In a given carrier, most of the CD4⁺ clones specific for a defined pp65 peptide had identical TCR nucleotide sequences. We used clonotype oligonucleotide probing to quantify the size of individual peptide-specific CD4⁺ clones in whole PBMC and in purified subpopulations of CD45RA^highCD45RO^low and CD45RA^lowCD45RO^high cells. Individual CD4⁺ T cell clones could be large (0.3–1.5% of all CD4⁺ T cells in PBMC) and were stable over time. Cells of a single clone were distributed in both the CD45RA^high and CD45RO^high subpopulations. In one carrier, the virus-specific clone was especially abundant in the small CD28^–CD45RA^high CD4⁺ T cell subpopulation. Our study demonstrates marked clonal expansion and phenotypic heterogeneity within daughter cells of a single virus-specific CD4⁺ T cell clone, which resembles that seen in the CD8⁺ T cell response against HCMV pp65.

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