Circulating bcr-abl-specific CD8+ T cells in chronic myeloid leukemia patients and healthy subjects

Abstract

BACKGROUND AND OBJECTIVES: The fusion oncoprotein bcr-abl that characterizes chronic myeloid leukemia (CML) is a leukemia-specific antigen, which may be immunogenic in vivo. KQSSKALQR and GFKQSSKAL, peptide sequences spanning the b3a2 bcr-abl junction, have affinity for HLA-A3 and HLA-B8, respectively, and we have shown the presence of KQSSKALQR on the surface of CML cells. We analyzed the existence of bcr-abl-specific T cells in vivo and correlated their presence to contemporary disease burden. DESIGN AND METHODS: We investigated circulating CD8+ T lymphocytes directed against the bcr-abl junction, using fluorochrome-labeled tetramers of HLA-A3 with KQSSKALQR and of HLA-B8 with GFKQSSKAL, and flow cytometry analysis. Using chromium-release assays and interferon-g ELISPOT assays, we also studied the functionality of these expanded T cells. RESULTS: Eight of 12 b3a2+ HLA-A3+ and/or HLA-B8+ CML patients studied serially on at least three occasions had bcr-abl junction-specific CD8+ T cells. Specific T cells were more likely to be found in patients with a low leukemic burden (p=0.03). Three of 18 HLA-A3+ and/or HLA-B8+ healthy donors had bcr-abl junction-specific T cells, though these were not detected in any of 13 subjects who were HLA-A3- and HLA-B8-. Bcr-abl-specific T cells were expandable in vitro in three of seven healthy donors and five of seven CML patients. INTERPRETATION AND CONCLUSIONS: Bcr-abl-specific T cells are detectable in CML patients, and might contribute to leukemic control. The occurrence of specific CD8+ T cells in some healthy donors might represent an immune response to occult BCR-ABL rearrangements.