Blood dendritic cells suppress NK cell function and increase the risk of leukemia relapse after hematopoietic cell transplantation.
NK cells play an important role in hematopoietic stem cell transplantation (HCT) and in cross talk with dendritic cells (DCs) to induce primary T cell response against infection. Therefore, we hypothesized that blood DCs should augment NK cell function and reduce the risk of leukemia relapse after HCT. To test this hypothesis, we conducted laboratory and clinical studies in parallel. We found that although, phenotypically, NK cells could induce DC maturation and DCs could in turn increase activating marker expression on NK cells, paradoxically, both BDCA1(+) myeloid DCs and BDCA4(+) plasmacytoid DCs suppressed the function of NK cells. Patients who received an HLA-haploidentical graft containing a larger number of BDCA1(+) DCs or BDCA4(+) DCs had a higher risk of leukemia relapse and poorer survival. Further experiments indicated that the potent inhibition on NK cell cytokine production and cytotoxicity was mediated in part through the secretion of IL-10 by BDCA1(+) DCs and IL-6 by BDCA4(+) DCs. These results have significant implications for future HCT strategies.
Perez-Martinez
Antonio
A
Division of Bone Marrow Transplantation and Cellular Therapy, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Iyengar
Rekha
R
Gan
Kwan
K
Chotsampancharoen
Thirachit
T
Rooney
Barbara
B
Holladay
Marti
M
Ramírez
Manuel
M
Leung
Wing
W
D000818:Animals; D018949:Antigens, CD1; D000954:Antigens, Surface / Q000032:analysis; D000970:Antineoplastic Agents / Q000008:administration & dosage; D015415:Biomarkers / Q000032:analysis; D002450:Cell Communication / Q000276:immunology; D018929:Cell Culture Techniques; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D006023:Glycoproteins; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D007938:Leukemia / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology; D012008:Recurrence; D015398:Signal Transduction / Q000276:immunology*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D018949:Antigens, CD1; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D015415:Biomarkers; C437944:CD1C protein, human; D006023:Glycoproteins; D015850:Interleukin-6; C478196:blood dendritic cell antigen 4, human; D016753:Interleukin-10