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Cell Stress and Chaperones : Volume 13, Issue 1, March 2008

Influence of Hsp70 and HLA-E on the killing of leukemic blasts by cytokine/Hsp70 peptide-activated human natural killer (NK) cells

Content Provider	Springer Nature Link
Author	Stangl, Stefan Gross, Catharina Pockley, Alan G. Asea, Alexzander A. Multhoff, Gabriele
Copyright Year	2008
Abstract	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.
Starting Page	221
Ending Page	230
Page Count	10
File Format	PDF
ISSN	13558145
Journal	Cell Stress and Chaperones
Volume Number	13
Issue Number	2
e-ISSN	14661268
Language	English
Publisher	Springer Netherlands
Publisher Date	2008-02-26
Publisher Place	Dordrecht
Access Restriction	Subscribed
Subject Keyword	Human Natural killer cells Cell surface molecules Cytotoxicity Tumor immunity Cancer Research Immunology Biochemistry Cell Biology Biomedicine general
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry

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