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Originally published online as doi:10.1189/jlb.0508285 on August 13, 2008

Published online before print August 13, 2008
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(Journal of Leukocyte Biology. 2008;84:1306-1315.)
© 2008 by Society for Leukocyte Biology

Maturation of dendritic cells depends on proteolytic cleavage by cathepsin X

Natasa Obermajer*, Urban Svajger{dagger}, Mathew Bogyo{ddagger}, Matjaz Jeras{dagger} and Janko Kos*,§,1

* University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia;
{dagger} Blood Transfusion Center of Slovenia, Ljubljana, Slovenia;
{ddagger} Department of Pathology, Stanford University School of Medicine, Stanford, California, USA; and
§ Jozef Stefan Institute, Department of Biotechnology, Ljubljana, Slovenia

1 Correspondence: Department of Pharmaceutical Biology, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia. E-mail: janko.kos{at}ffa.uni-lj.si

The maturation status of dendritic cells (DCs) is crucial for effective antigen presentation and initiation of the primary immune response. Maturation stimuli cause the adhesion of immature DCs to the extracellular matrix, which is accompanied by recruitment of the CD11b/CD18 [macrophage antigen-1 (Mac-1)] integrin receptor, cytoskeleton reorganization, and podosome formation. Cathepsin X, a cysteine protease expressed in DCs and other APCs, is involved in Mac-1 activation. We have shown that during maturation, cathepsin X translocates to the plasma membrane of maturing DCs, enabling Mac-1 activation and consequently, cell adhesion. In mature DCs, cathepsin X redistributes from the membrane to the perinuclear region, which coincides with the de-adhesion of DCs, formation of cell clusters, and acquisition of the mature phenotype. Inhibition of cathepsin X activity during DC differentiation and maturation resulted in an altered phenotype and function of mature DCs. It reduced surface expression of costimulatory molecules, increased expression of inhibitory Ig-like transcripts 3 and 4 (ILT3 and ILT4), almost completely abolished cytokine production, diminished migration, and reduced the capacity of DCs to stimulate T lymphocytes. These results stress the importance of cathepsin X in regulating DC adhesion, a crucial event for their maturation and T cell activation.

Key Words: carboxypeptidase • integrin • adhesion • antigen-presenting cell






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