CTL clones isolated from an HLA-Cw-mismatched bone marrow transplant recipient with acute graft-versus-host disease.
HLA-Cw disparity in a donor increases the risk of acute graft-vs-host disease (GVHD) after bone marrow transplantation. Acute GVHD is mediated by donor CTLs. However, mismatched HLA-Cw-specific CTLs generated in posttransplant recipients who developed acute GVHD have not been characterized in detail. In this study, CTL clones isolated from a recipient at the onset of acute GVHD who was transplanted from an HLA-A, -B, and -DRB1-matched, HLA-Cw-mismatched (recipient, Cw*0303/Cw*0702; donor, Cw*0801/Cw*0702), unrelated donor were characterized. The seven isolated CTLs, including CD4(+), CD8(+), and CD4(+)CD8(+) T lymphocytes, lysed recipient cells, HLA-Cw*0303-transfected 721.211 cells, and HLA-Cw*0303-transfected donor cells, but not untransfected 721.211 cells or donor cells. Thus, all CTLs recognized the mismatched Cw*0303 molecule as an alloantigen. The sequences of Cw*0303 and Cw*0801 differ by 16 aas. Stimulation of CTLs by COS cells transfected with Cw*0303 cDNA constructs demonstrated that Cw*0303 mutants in which individual amino acids constituting peptide-binding pockets were substituted with the corresponding Cw*0801 amino acids significantly decreased IFN-gamma production by all CTLs, whereas Cw*0303 mutants bearing Cw*0801 amino acids outside the positions constituting peptide-binding pockets stimulated all CTLs to the same degree as the wild-type Cw*0303 construct. These data suggest that all CTLs recognized the Cw molecule in a peptide-dependent manner. ELISPOT revealed that Cw*0303-reactive T cells accounted for one-half of the total of alloreactive T cells in the blood during GVHD. Taken together, non-self Cw-specific CTL clones with a variety of phenotypes and peptide specificities can be generated in posttransplant recipients with acute GVHD.
Sugimoto
Kyoko
K
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Murata
Makoto
M
Terakura
Seitaro
S
Naoe
Tomoki
T
D000208:Acute Disease; D000328:Adult; D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology*; D015236:HLA-C Antigens / Q000009:adverse effects / Q000235:genetics; D006801:Humans; D007519:Isoantigens / Q000235:genetics / Q000378:metabolism; D008912:Minor Histocompatibility Loci / Q000235:genetics; D008969:Molecular Sequence Data; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
D015236:HLA-C Antigens; D007519:Isoantigens