Search

Minor histocompatibility antigen (MiHAg) differences between donor and recipient in MHC-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT) often result in graft-versus-host disease (GVHD). While MiHAg-specific T-cell responses can in theory be directed against a large number of polymorphic differences between donor and recipient, in practice, T-cell responses against only a small set of MiHAgs appear to dominate the immune response, and it has been suggested that immunodominance may predict an important contribution to the development of GVHD. Here, we addressed the feasibility of graft engineering by ex vivo removal of T cells with 1 or more defined antigen specificities in a well-characterized experimental HSCT model (B6 → BALB.B). We demonstrate that immunodominant H60- and H4-specific CD8+ T-cell responses can be effectively suppressed through MHC class I tetramer–mediated purging of the naive CD8+ T cell repertoire. Importantly, the development of GVHD occurs unimpeded upon suppression of the immunodominant MiHAg-specific T-cell response. These data indicate that antigen-specific graft engineering is feasible, but that parameters other than immunodominance may be required to select T-cell specificities that are targeted for removal.

During immunosuppression, cytomegalovirus (CMV) can reactivate and cause serious clinical problems. Normally, abundant virus replication is suppressed by immune effector mechanisms. To study the interaction between CD8+ T cells and persisting viruses, frequencies and phenotypes of CMV-specific CD8+ T cells were determined in healthy individuals and compared to those in renal transplant recipients. In healthy donors, function of circulating virus-specific CD8+ T cells, as measured by peptide-induced interferon γ (IFN-γ) production, but not the number of virus-specific T cells enumerated by binding of specific tetrameric peptide/HLA complexes, correlated with the number of CMV-specific IFN-γ–secreting CD4+ helper T cells. Circulating CMV- specific CD8+ T cells did not express CCR7 and may therefore not be able to recirculate through peripheral lymph nodes. Based on coexpression of CD27 and CD45R0 most CMV-specific T cells in healthy donors appeared to be memory-type cells. Remarkably, frequencies of CMV-specific CD8+ T cells were significantly higher in immunosuppressed individuals than in healthy donors. In these patients CMV-specific cells predominantly had an effector phenotype, that is, CD45R0+CD27−CCR7− or CD45RA+CD27−CCR7− and contained both granzyme B and perforin. Our data show that in response to immunosuppressive medication quantitative and qualitative changes occur in the CD8+ T-cell compartment. These adaptations may be instrumental to maintain CMV latency.