An alloresponse in humans is dominated by cytotoxic T lymphocytes (CTL) cross-reactive with a single Epstein-Barr virus CTL epitope: implications for graft-versus-host disease.
The phenomenon of T cell allorecognition is difficult to accommodate within the framework of a T cell repertoire positively selected in the thymus, unless allorecognition results from the cross-reactions of self-major histocompatibility complex restricted T cells. Herein, we demonstrate the dual specificity of cytotoxic T lymphocyte (CTL) clones for the immunodominant Epstein-Barr virus (EBV) epitope FLRGRAYGL, presented on HLA-B8, and the alloantigen HLA-B*4402. CTL which recognized peptide FLRGRAYGL in association with HLA-B8 could be reactivated in vitro from healthy individuals who had been exposed previously to EBV, using stimulator cells expressing the cross-reacting alloantigen HLA-B*4402. Limiting dilution analysis of the alloresponse to HLA-B*4402 in eight healthy individuals revealed that HLA-B8+, EBV-sero+ donors had higher CTL precursor frequencies for alloantigen HLA-B*4402 than EBV-sero- control donors. It is surprising that the majority (65-100%) of anti-HLA-B*4402 CTL, generated in limiting dilution mixed lymphocyte reactions between responder cells from HLA-B8+, EBV-sero+ individuals and HLA-B*4402+ stimulators, also recognized the EBV CTL epitope FLRGRAYGL/HLA-B8. In contrast to previous studies showing extensive diversity in the T cell repertoire against individual alloantigens, these data demonstrate that the response to an alloantigen can be dominated by CTL cross-reactive with a single viral epitope, thus illustrating a possible mechanism for the frequent clinical association between herpesvirus exposure and graft-versus-host disease after bone marrow transplants.
Burrows
S R
SR
Queensland Institute of Medical Research, Bancroft Centre, Herston, Brisbane, Australia.
Khanna
R
R
Burrows
J M
JM
Moss
D J
DJ
D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions; D000939:Epitopes / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology; D015795:HLA-B8 Antigen / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D008969:Molecular Sequence Data; D012307:Risk Factors; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000956:Antigens, Viral; D000939:Epitopes; D015235:HLA-B Antigens; D015795:HLA-B8 Antigen; D007519:Isoantigens