International Immunology Advance Access originally published online on July 18, 2006
International Immunology 2006 18(9):1347-1354; doi:10.1093/intimm/dxl071
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Constitutively polarized granules prime KHYG-1 NK cells
1 Department of Medical Oncology and Hematology, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Suite 5-211, Toronto, ON M5G2M9, Canada
2 Division of Experimental Therapeutics, Toronto General Research Institute, University of Toronto, Toronto, ON M5G2M1, Canada
3 Institute of Medical Science, University of Toronto, Toronto, ON M5G2M1, Canada
4 Research and Development, Canadian Blood Services, Toronto Centre, Toronto, ON M5G2M1, Canada
5 Present address: Division of Biomedical Sciences, Johns Hopkins in Singapore, 31 Biopolis Way, #02-01, The Nanos, Singapore 138669
Correspondence to: G. Suck; E-mail: garnet.suck{at}uhn.on.ca
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.
Keywords: colcemid, cytotoxic granules, ERK, KHYG-1, microtubules, NK cell, NKG2D, NKp44, perforin
* These authors contributed equally to this work.
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