DDX3Y encodes a class I MHC-restricted H-Y antigen that is expressed in leukemic stem cells

The Y chromosome encodes male-specific minor histocompatibility (H-Y) antigens that stimulate Tand B-lymphocyte responses after sex-mismatched allogeneic hematopoietic cell transplantation (HCT). A CD8⁺ cytotoxic T lymphocyte (CTL) clone that recognizes a novel HLAB^*2705- restricted H-Y antigen encoded by the DDX3Y gene was isolated from a male who had received a hematopoietic cell graft from his human leukocyte antigen (HLA)-identical sister. The antigenic peptide is a decamer that differs from the homologous DDX3X-encoded peptide at 4 positions. Expression of DDX3Y and of the H-Y epitope that it encodes was examined by quantitative polymerase chain reaction (PCR) and by CTL recognition assays. Expression of DDX3Y\s detected in all myeloid and lymphoid leukemic cells that carry an intact Y chromosome. Moreover, the 0DX3V-encoded H-Y epitope is presented on the surface of both myeloid and lymphoid leukemic cells from male HLA-B^*2705 ⁺ patients. DDX3Yspecific CTLs prevent engraftment of human acute leukemia in nonobese diabetic/severe combined immune deficient mice, demonstrating that the DDX3Y-encoded H-Y antigen is also expressed in leukemic stem cells. These results demonstrate that CD8⁺ T-cell responses against DDX3Y have the potential to contribute to graft-versus-leukemia (GVL) activity after female into male allogeneic HCT. This study is registered at http://clinicaltrials. gov as NCT00107354.