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.
Crompton
Laura
L
Cancer Research UK, Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom.
Khan
Naeem
N
Khanna
Rajiv
R
Nayak
Laxman
L
Moss
Paul A H
PA
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D018929:Cell Culture Techniques; D002999:Clone Cells; D003586:Cytomegalovirus Infections / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005333:Fetus; D005347:Fibroblasts / Q000276:immunology; D015809:HLA-DR7 Antigen / Q000276:immunology; D006801:Humans; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012867:Skin / Q000166:cytology / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*
D015809:HLA-DR7 Antigen; D011948:Receptors, Antigen, T-Cell; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; D012313:RNA