title: Functional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation.
abstract: Antigens implicated in the graft-versus-leukemia (GVL) effect in chronic myeloid leukemia (CML) include WT1, PR1, and BCR-ABL. To detect very low frequencies of these antigen-specific CD8+ T cells, we used quantitative polymerase chain reaction (qPCR) to measure interferon-gamma (IFN-gamma) mRNA production by peptide-pulsed CD8+ T cells from HLA-A*0201+ healthy volunteers and from patients with CML before and after allogeneic stem cell transplantation (SCT). Parallel assays using cytomegalovirus (CMV) pp65 tetramers demonstrated the IFN-gamma copy number to be linearly related to the frequency of tetramer-binding T cells, sensitive to frequencies of 1 responding CD8+ T cell/100 000 CD8+ T cells. Responses to WT1 and PR1 but not BCR-ABL were detected in 10 of 18 healthy donors. Responses to WT1, PR1, or BCR-ABL were observed in 9 of 14 patients with CML before SCT and 5 of 6 after SCT, often to multiple epitopes. Responses were higher in patients with CML compared with healthy donors and highest after SCT. These antigen-specific CD8+ T cells comprised central memory (CD45RO+CD27+CD57-) and effector memory (CD45RO-CD27-CD57+) T cells. In conclusion, leukemia-reactive CD8+ T cells derive from memory T cells and occur at low frequencies in healthy individuals and at higher frequencies in patients with CML. The increased response in patients after SCT suggests a quantitative explanation for the greater effect of allogeneic SCT.
authors.affiliation: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.forename: Matthias
authors.initials: M
authors.lastname: Grube
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sconocchia
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Ko
authors.initials: K
authors.lastname: Yamada
authors.forename: Jan
authors.initials: J
authors.lastname: Melenhorst
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.forename: Nancy
authors.initials: N
authors.lastname: Hensel
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D017252:CD3 Complex / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000097:blood*; D015789:HLA-A2 Antigen; D006801:Humans; D007156:Immunologic Memory; D007938:Leukemia / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy*; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors
chemical_list: D017252:CD3 Complex; D016827:CD8 Antigens; D018076:DNA, Complementary; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D012313:RNA