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Published online before print October 4, 2005
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*The Inflammation Program, Divisions of ¶Infectious Diseases and Rheumatology, ||Departments of Internal Medicine, Physiology and Biophysics, and the Graduate Programs in Immunology and **Molecular Biology, University of Iowa Carver College of Medicine and Iowa City Veterans Affairs Medical Center, Coralville; and Department of Microbiology and Immunology, University of Miami, Florida
@ To whom correspondence should be addressed. E-mail: david-kusner{at}uiowa.edu.
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Abstract |
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Dendritic cells (DC) are professional antigen-presenting cells, which activate the adaptive immune system. Upon receiving a danger signal, they undergo a maturation process, which increases their antigen presentation capacity, but the responsible regulatory mechanisms remain incompletely understood. A Ca2+-calmodulin (Cam)-Cam kinase II (CamK II) pathway regulates phagosome maturation in macrophages, and this pathway is inhibited by pathogenic microbes. Our hypothesis is that signal transduction events, which control phagosome maturation, also regulate antigen presentation. Stimulation of primary human DC or the human DC line KG-1, with particulate antigen, resulted in the activation of CamK II and its localization to the phagosome and plasma membrane. Two mechanistically distinct inhibitors of CamK II significantly reduced DC maturation, as determined by up-regulation of surface costimulatory and major histocompatibility complex (MHC) class II molecules and secretion of cytokines. Confocal microscopy demonstrated that the CamK II inhibitors blocked the antigen-induced increase in total cellular MHC class molecules as well as their trafficking to the plasma membrane. Inhibition of CamK II was associated with decreased presentation of particulate and soluble MHC class II-restricted antigen, with a greater effect on the former. These data support a model in which CamK II regulates critical stages of the maturation and antigen presentation capacity of human DC, particularly in response to stimulation via phagocytosis.
Key Words: signal transduction • cell differentiation • antigen presentation/processing • cytokines • MHC
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