International Immunology Advance Access published online on July 18, 2006
International Immunology, doi:10.1093/intimm/dxl071
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1 Department of Medical Oncology and Hematology, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Suite 5-211, Toronto, ON M5G2M9, Canada; Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, ON M5G2M1, Canada; Present address: Division of Biomedical Sciences, Johns Hopkins in Singapore, 31 Biopolis Way, #02-01, The Nanos, Singapore 138669
* To whom correspondence should be addressed. The major mechanism for NK cell lysis of tumor cells is granule-mediated cytotoxicity. Polarization of granules is a prelude to the release of their cytotoxic contents in response to target-cell binding. We describe the novel observation of constitutive granule polarization in the cytotoxic NK cell line, KHYG-1. Continuous degranulation of KHYG-1 cells, however, does not occur and still requires target-cell contact. Disruption of microtubules with colcemid is sufficient to disperse the granules in KHYG-1 and significantly decreases cytotoxicity. A similar effect is not obtained by inhibiting extracellular signal-related kinase 2 (ERK2), the most distal kinase investigated in the cytolytic pathway. Disruption of microtubules significantly down-regulates activation receptors, NKp44 and NKG2D, implicating them as potential microtubule-trafficking receptors. Such changes in upstream receptor expression may have caused deactivation of ERK2, since NKG2D cross-linking also leads to receptor down-regulation and diminished ERK phosphorylation. Thus, a functional role for NKG2D in KHYG-1 cytotoxicity is demonstrated. Moreover, the novel primed state may contribute to the high cytotoxicity exhibited by KHYG-1. *These authors contributed equally to this work.
Received January 14, 2006
Accepted June 22, 2006
Article
Constitutively polarized granules prime KHYG-1 NK cells
Garnet Suck 1 *, Donald R. Branch 2 *, Paola Aravena 3, Mark Mathieson 4, Simone Helke 3, and Armand Keating 5 *
2 Institute of Medical Science, University of Toronto, Toronto, ON M5G2M1, Canada; Research and Development, Canadian Blood Services, Toronto Centre, Toronto, ON M5G2M1, Canada
3 Department of Medical Oncology and Hematology, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Suite 5-211, Toronto, ON M5G2M9, Canada
4 Institute of Medical Science, University of Toronto, Toronto, ON M5G2M1, Canada
5 Department of Medical Oncology and Hematology, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Suite 5-211, Toronto, ON M5G2M9, Canada; Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, ON M5G2M1, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5G2M1, Canada
Garnet Suck, E-mail: garnet.suck{at}uhn.on.ca
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