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Blood, 1 February 2006, Vol. 107, No. 3, pp. 1184-1191.
Prepublished online as a Blood First Edition Paper on September 29, 2005; DOI 10.1182/blood-2005-03-1337.
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Submitted April 1, 2005
Accepted September 21, 2005
Immunoselection by natural killer cells of PIG-A mutant cells missing stress-inducible ULBP
Nobuyoshi Hanaoka, Tatsuya Kawaguchi, Kentaro Horikawa, Shoichi Nagakura, Hiroaki Mitsuya, and Hideki Nakakuma*
Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
Devision of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan
Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
* Corresponding author; email: hnakakum{at}wakayama-med.ac.jp.
The mechanism by which paroxysmal nocturnal hemoglobinuria (PNH) clones expand is unknown. PNH clones harbor PIG-A mutations and do not synthesize glycosylphosphatidylinositol (GPI), resulting in deficiency of GPI-linked membrane proteins. GPI-deficient blood cells often expand in patients with aplastic anemia who sustain immune-mediated marrow injury putatively induced by cytotoxic cells, hence suggesting that the injury allows PNH clones to expand selectively. We previously reported that leukemic K562 cells preferentially survived natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIG-A mutations. We herein show that the survival is ascribable to the deficiency of stress-inducible GPI-linked membrane proteins ULBP1 and ULBP2 that activate NK and T cells. The ULBPs were detected on GPI-expressing but not on GPI-deficient K562 cells. In the presence of antibodies to either the ULBPs or their receptor NKG2D on NK cells, GPI-expressing cells were as less NK-sensitive as GPI-deficient cells. NK cells therefore spared ULBP-deficient cells in vitro. The ULBPs were identified only on GPI-expressing blood cells of a proportion of PNH patients but none of healthy individuals. Granulocytes of the patients partly underwent killing by autologous cytotoxic cells, implying ULBP-associated blood cell injury. In this setting, the lack of ULBPs may allow immunoselection of PNH clones.
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