Selective T-cell-receptor gene usage in allorecognition and graft-versus-host disease

Immune recognition of foreign HLA molecules is initiated by T cell recognition mediated by alloreactive T cell receptor (TCR) molecules. We analyzed the diversity of TCR expression in the clinical setting of allorecognition in a patient with acute graft-versus-host disease following bone marrow transplantation. Nearly 200 TCR transcripts from peripheral blood lymphocytes were cloned and sequenced at two time points during GVHD. HLA genes in the transplant donor and the recipient were mismatched for a very specific HLA-DR subtype: HLA-DRB1 genes in the donor (DR4/Dw4) and the recipient (DR4/Dw14) encode HLA molecules that differ at only two amino acids, providing a very restricted target for allorecognition. We also studied TCR genes from five T cell clones derived in vitro from mixed lymphocyte cultures between Dw4-positive responder and Dw14-positive stimulator cells. Comparisons of the derived TCR sequences implicate nonrandom patterns of TCR selection both in vivo and in vitro.