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  • Title: CTL clones isolated from an HLA-Cw-mismatched bone marrow transplant recipient with acute graft-versus-host disease.
    Author: Sugimoto K, Murata M, Terakura S, Naoe T.
    Journal: J Immunol; 2009 Nov 01; 183(9):5991-8. PubMed ID: 19812210.
    Abstract:
    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.
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