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JNK MAP kinase activation is required for MTOC and granule polarization in NKG2D-mediated NK cell cytotoxicity

Changlin Li1, Baoxue Ge, Matthew Nicotra

  • 1Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 22, 2008
PubMed

Insights

Natural killer (NK) cell cytotoxicity relies on the NKG2D receptor pathway. This study reveals that JNK and ERK mitogen-activated protein (MAP) kinase pathways are crucial for NK cell-mediated killing and immune synapse formation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The activating receptor NKG2D is a key pathway for natural killer (NK) cell-mediated cytotoxicity.
  • Understanding the downstream signaling events following NKG2D engagement is critical for deciphering NK cell activation.

Purpose of the Study:

  • To investigate the specific mitogen-activated protein (MAP) kinase signaling pathways involved in NKG2D-mediated NK cell cytotoxicity.
  • To determine the role of these pathways in the formation of the immune synapse and cytotoxic granule polarization.

Main Methods:

  • Utilized the human NKL tumor cell line and K562 target cells for studying NKG2D-ligand interactions.
  • Employed selective inhibitors for JNK MAP kinase, Src protein tyrosine kinases, and phospholipase PLCgamma.
  • Assessed cytotoxicity, microtubule organizing center (MTOC) movement, granzyme B, and paxillin localization to the immune synapse.

Main Results:

  • NKG2D ligation strongly activated both JNK and ERK MAP kinases.
  • Inhibition of JNK MAP kinase significantly reduced NKG2D-mediated cytotoxicity and blocked the polarization of MTOC, granzyme B, and paxillin to the immune synapse.
  • Upstream inhibition of Src kinases and PLCgamma also impaired NKG2D-induced JNK activation.

Conclusions:

  • Activation of both JNK and ERK MAP kinase pathways is essential for NKG2D-induced NK cell cytotoxicity.
  • These MAP kinase pathways are required for the proper polarization of cytotoxic granules and the MTOC, facilitating efficient immune synapse formation and target cell killing.

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