STRUCTURE OF TCR ON TLYMPHOCYTES HARNESSING GRAFT-VERSUS-LEUKEMIA EFFECT

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We have found that recipients of allogeneic hematopoietic stem cell grafts have a skewing of the αβ TCR repertoire after transplant and this is a result of the proliferation of donor-derived mature T lymphocytes which can survive in recipients for several years. Expansion of the population of donor-derived TCRαβ+ T clones from a cytomegalovirus (CMV)-seropositive bone marrow donor was observed in a CMV-seropositive recipient when developing CMV-associated disease after transplantation. These results suggest that the clonal expansion of TCRαβ+ T cells and resulting skewed αβ TCR repertoire in peripheral blood following allogeneic hematopoietic stem cell transplantation (HSCT) primarily reflect the response to microorganisms. We have also found that stable clonal expansion of Vδ1+ _YδT lymphocytes persisted for several years after human allo-HSCT. CDR3 size spectratyping analysis revealed that twenty-three out of forty-two patients had highly skewed TCR repertoires of the Vδ1+ T cells. There was no apparent association between the oligoclonality of Vδ1+ TCRs and clinical outcome such as GVHD and leukemia relapse. In eight out of seventeen patients examined, the -WGI-amino acid sequence was observed in the CDR3 region of TCRs of clonally expanded Vδ1+ T cells. The -YWG-sequence was observed in four patients. All recipients examined were serologically positive for EBV-VCA IgG and EBNA. Autologous EBV transformed B cells could induce the expansion of Vδ1+ T cells. The CDR3 size distribution patterns of Vδ1+ TCRs became skewed after stimulation with autologous EBV-LCL, and the T cell clone with the -LEEYWGLPH-CDR3 sequence predominated in the culture with autologous EBV-LCL. These results suggest the CDR3 structure may contribute to recognition of EBV-associated antigens by Vδ1+ T cells. Skewing of the Vδ1+ TCR after allo-HSCT may be the result of the response to infectious antigens widely existing in humans such as EBV.