Cross-recognition of human alloantigen by cytomegalovirus glycoprotein-specific CD4+ cytotoxic T lymphocytes: implications for graft-versus-host disease.

Presence of the HLA-DR7 allele in patients who receive transplants has been proposed as a risk factor for human cytomegalovirus (HCMV)-associated complications; however, the precise mechanism of this increased risk remains unresolved. Here we show that HLA-DR7-restricted HCMV-specific CD4(+) cytotoxic T lymphocytes (CTLs) can display an unusual dual specificity toward a glycoprotein-B (gB) epitope and the alloantigen HLA-DR4. However, no HLA-DR4-specific alloreactivity was observed when the gB-specific CTLs were generated from virus carriers expressing both HLA-DR7 and DR4 alleles. This most likely demonstrates the clonal inactivation of potentially self-reactive T cells in humans. Fine specificity analysis showed that gB-specific CTLs from HLA-DR7(+)/DR4(-) individuals displayed a distinct pattern of recognition when compared with CTLs from HLA-DR7(+)/DR4(+) individuals, presumably evading an area of the epitope that mimics a structure presented on HLA-DR4. These data illustrate a possible mechanism for the clinical association between HCMV and graft-versus-host disease.