The Immunomodulatory Action of Sialostatin L on Dendritic Cells Reveals Its Potential to Interfere with Autoimmunity

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-gamma 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 Journal of Immunology, 2009, 182: 7422-7429.

Intramural Research Program of the Division of Intramural Research

Intramural Research Program of the Division of Intramural Research

U.S. National Institutes of Health (NIH)

National Institute of Allergy and Infectious Diseases (NIAID/NIH)

U.S. National Institutes of Health (NIH)

National Institutes of Health (NIH)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

CNPq Conselho Nacional de Pesquisas[472477/2007-2]

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

CNPq Conselho Nacional de Pesquisas[565496/2008-5]

Fundacao de Apoio a Pesquisa Cientifica e Tecnologica do Estado de Santa Catarina-FAPESC[04524/2008-1]

Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC)

WHO World Health Organization/TDR[2008-8734-0]

WHO World Health Organization/TDR