| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065; and
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461
Microglia are resident macrophage-like APCs of the CNS. To avoid escalation of inflammatory processes and bystander damage within the CNS, microglia-driven inflammatory responses need to be tightly regulated and both spatially and temporally restricted. Following traumatic, infectious, and autoimmune-mediated brain injury, NK cells have been found in the CNS, but the functional significance of NK cell recruitment and their mechanisms of action during brain inflammation are not well understood. In this study, we investigated whether and by which mechanisms human NK cells might edit resting and activated human microglial cells via killing in vitro. IL-2-activated NK cells efficiently killed both resting allogeneic and autologous microglia in a cell-contact-dependent manner. Activated NK cells rapidly formed synapses with human microglial cells in which perforin had been polarized to the cellular interface. Ab-mediated NKG2D and NKp46 blockade completely prevented the killing of human microglia by activated NK cells. Up-regulation of MHC class I surface expression by TLR4 stimulation protected microglia from NK cell-mediated killing, whereas MHC class I blockade enhanced cytotoxic NK cell activity. These data suggest that brain-infiltrating NK cells might restrict innate and adaptive immune responses within the human CNS via elimination of resting microglia.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 J.D.L. is a recipient of the Dana Foundation and Irvington Institute’s Human Immunology Fellowship from the Cancer Research Institute and is supported by a Pilot Grant from the National Multiple Sclerosis Society (PP1145) and an Institutional Clinical and Translational Science Pilot and Collaborative Project Grant (to the Rockefeller University Hospital). C.S.R. is the Wollowick Family Professor in Multiple Sclerosis Research. C.M. is supported by the Dana Foundation Neuroimmunology Program, the Arnold and Mabel Beckman Foundation, the Alexandrine and Alexander Sinsheimer Foundation, the Burroughs Wellcome Fund, the Starr Foundation, the National Cancer Institute (R01CA108609 and R01CA101741), the National Institute of Allergy and Infectious Diseases (RFP-NIH-NIAID-DAIDS-BAA-06-19), the Foundation for the National Institutes of Health (Grand Challenges in Global Health), and an Institutional Clinical and Translational Science Award (to the Rockefeller University Hospital).
2 Address correspondence and reprint requests to Dr. Christian Münz at the current address: Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zürich, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail address: munzc{at}rockefeller.edu
3 Abbreviations used in this paper: MG, microglia; BBB, blood-brain barrier; EAE, experimental autoimmune encephalomyelitis; DC, dendritic cell; RE, relative enrichment; TP3, TO-PRO-3 iodide.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
