| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Laboratory of Experimental Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil;
Section of Vector Biology, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD 20852;
Division of Immunology, Department of Microbiology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil;
Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892;
¶ Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892; and
|| Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
Sialostatin L (SialoL) is a secreted cysteine protease inhibitor identified in the salivary glands of the Lyme disease vector Ixodes scapularis. In this study, we reveal the mechanisms of SialoL immunomodulatory actions on the vertebrate host. LPS-induced maturation of dendritic cells from C57BL/6 mice was significantly reduced in the presence of SialoL. Although OVA degradation was not affected by the presence of SialoL in dendritic cell cultures, cathepsin S activity was partially inhibited, leading to an accumulation of a 10-kDa invariant chain intermediate in these cells. As a consequence, in vitro Ag-specific CD4+ T cell proliferation was inhibited in a time-dependent manner by SialoL, and further studies engaging cathepsin S–/– or cathepsin L–/– dendritic cells confirmed that the immunomodulatory actions of SialoL are mediated by inhibition of cathepsin S. Moreover, mice treated with SialoL displayed decreased early T cell expansion and recall response upon antigenic stimulation. Finally, SialoL administration during the immunization phase of experimental autoimmune encephalomyelitis in mice significantly prevented disease symptoms, which was associated with impaired IFN-
and IL-17 production and specific T cell proliferation. These results illuminate the dual mechanism by which a human disease vector protein modulates vertebrate host immunity and reveals its potential in prevention of an autoimmune disease.
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 This work was supported by funding from the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. A.B. received funding from Conselho Nacional de Pesquisas Grants 472477/2007-2 and 565496/2008-5, Fundação de Apoio à Pesquisa Científica e Tecnológica do Estado de Santa Catarina Grant 04524/2008-1, and World Health Organization/TDR Grant 2008-8734-0.
2 Address correspondence and reprint requests to Dr. Anderson Sá-Nunes, Laboratório de Imunologia Experimental, Departamento de Imunologia, Instituto de Ciências Biomêdicas IV, Cidade Universitária, Avenida Prof. Lineu Prestes 1730, São Paulo, São Paulo 055908-900, Brazil. E-mail address: sanunes{at}usp.br or Dr. Michalis Kotsyfakis, 12735 Twinbrook Parkway, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Twinbrook III, Room 2E-28, Rockville, MD 20852. E-mail address: mkotsyfakis{at}mail.nih.gov
3 Abbreviations used in this paper: SialoL, sialostatin L; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; Ii, invariant chain; LN, lymph node; MOG, myelin oligodendrocyte glycoprotein; WT, wild type.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
