PMID- 18759005 OWN - NLM STAT- MEDLINE DCOM- 20091021 LR - 20240209 IS - 1466-1268 (Electronic) IS - 1355-8145 (Print) IS - 1355-8145 (Linking) VI - 13 IP - 2 DP - 2008 Summer TI - Influence of Hsp70 and HLA-E on the killing of leukemic blasts by cytokine/Hsp70 peptide-activated human natural killer (NK) cells. PG - 221-30 LID - 10.1007/s12192-007-0008-y [doi] AB - This study compared the effects of the human 70-kDa stress protein (Hsp70) peptide, TKDNNLLGRFELSG (TKD), proinflammatory cytokines, or a combination of both on the repertoire of receptors expressed by human natural killer (NK) cells and their capacity to kill human CX colon carcinoma cells, K562 erythroleukemic cells, and leukemic blasts from two patients with acute myelogenous leukemia. Low-dose interleukin (IL) 2/IL-15 and TKD increase the expression density of activatory (NKG2D, NKp30, NKp44, NKp46, CD94/NKG2C) and inhibitory (CD94/NKG2A) receptors on NK cells. Concomitantly, IL-2/TKD treatment enhances the cytotoxicity of NK cells (as reflected by their secretion of granzyme B) against Hsp70 membrane-positive and human leukocyte antigen (HLA)-E membrane-negative (Hsp70(+)/HLA-E(-)) CX(+) and K562 cells. However, it had no effect on the responsiveness to Hsp70(-)/HLA-E(-) CX(-) cells over that induced by IL-2 alone. The cytotoxicity of IL-2/TKD-activated, purified NK cells and peripheral blood mononuclear cells against Hsp70(+)/HLA-E(+) leukemic blasts was weaker than that against Hsp70(+)/HLA-E(-) K562 cells. Hsp70-blocking and HLA-E transfection experiments confirmed membrane-bound Hsp70 as being a recognition/activatory ligand for NK cells, as cytotoxicity was reduced by the presence of the anti-Hsp70 monoclonal antibody cmHsp70.2 and by inhibiting Hsp70 synthesis using short interference ribonucleic acid. HLA-E was confirmed as an inhibitory ligand, as the extent of NK cell-mediated lysis of K562 cell populations that had been transfected with HLA-E(R) or HLA-E(G) alleles was dependent on the proportion of HLA-E-expressing cells. These findings indicate that Hsp70 (as an activatory molecule) and HLA-E (as an inhibitory ligand) expression influence the susceptibility of leukemic cells to the cytolytic activities of cytokine/TKD-activated NK cells. FAU - Stangl, Stefan AU - Stangl S AD - Department of Radiotherapy/ Radiooncology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaningerstrasse 22, Munich, Germany. FAU - Gross, Catharina AU - Gross C FAU - Pockley, Alan G AU - Pockley AG FAU - Asea, Alexzander A AU - Asea AA FAU - Multhoff, Gabriele AU - Multhoff G LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20080226 PL - Netherlands TA - Cell Stress Chaperones JT - Cell stress & chaperones JID - 9610925 RN - 0 (Antibodies, Monoclonal) RN - 0 (HLA Antigens) RN - 0 (HSP70 Heat-Shock Proteins) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Interleukin-15) RN - 0 (Interleukin-2) RN - 0 (Neoplasm Proteins) RN - 0 (Peptide Fragments) RN - 0 (RNA, Small Interfering) RN - 0 (Recombinant Fusion Proteins) SB - IM MH - Acute Disease MH - Adenocarcinoma/immunology/pathology MH - Alleles MH - Antibodies, Monoclonal/pharmacology MH - Colonic Neoplasms/immunology/pathology MH - Cytotoxicity, Immunologic/drug effects MH - HLA Antigens/*immunology MH - HSP70 Heat-Shock Proteins/antagonists & inhibitors/*immunology MH - Histocompatibility Antigens Class I/*immunology MH - Humans MH - Immunologic Surveillance MH - Interleukin-15/pharmacology MH - Interleukin-2/pharmacology MH - K562 Cells/immunology MH - Killer Cells, Natural/drug effects/*immunology MH - Leukemia, Myeloid/immunology/pathology MH - Leukocytes, Mononuclear/drug effects/immunology MH - Neoplasm Proteins/immunology/*physiology MH - Neoplastic Stem Cells/*immunology MH - Peptide Fragments/pharmacology MH - RNA, Small Interfering/pharmacology MH - Recombinant Fusion Proteins/immunology/physiology MH - T-Lymphocytes, Cytotoxic/drug effects/immunology MH - Transfection MH - HLA-E Antigens PMC - PMC2673894 EDAT- 2008/09/02 09:00 MHDA- 2009/10/22 06:00 PMCR- 2008/12/01 CRDT- 2008/09/02 09:00 PHST- 2007/11/07 00:00 [received] PHST- 2007/12/26 00:00 [accepted] PHST- 2007/12/20 00:00 [revised] PHST- 2008/09/02 09:00 [pubmed] PHST- 2009/10/22 06:00 [medline] PHST- 2008/09/02 09:00 [entrez] PHST- 2008/12/01 00:00 [pmc-release] AID - S1355-8145(23)02183-1 [pii] AID - 8 [pii] AID - 10.1007/s12192-007-0008-y [doi] PST - ppublish SO - Cell Stress Chaperones. 2008 Summer;13(2):221-30. doi: 10.1007/s12192-007-0008-y. Epub 2008 Feb 26.