CD4+ T cells specific for glycoprotein B from cytomegalovirus exhibit extreme conservation of T-cell receptor usage between different individuals.

Antigen-specific CD8(+) cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4(+) T cells. CD4(+) T cells predominantly have a helper immune role, but a cytotoxic CD4(+) T-cell subset has been characterized, and we have studied the cytotoxic CD4(+) T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4(+) T-cell response that averages 3.6% of the total CD4(+) T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4(+) cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4(+) T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4(+) T cells thus parallels that of CD8(+) subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7(+) patients with CD4(+) T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder.