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.
Sá-Nunes
Anderson
A
Department of Immunology, Laboratory of Experimental Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Bafica
André
A
Antonelli
Lis R
LR
Choi
Eun Young
EY
Francischetti
Ivo M B
IM
Andersen
John F
JF
Shi
Guo-Ping
GP
Chavakis
Triantafyllos
T
Ribeiro
José M
JM
Kotsyfakis
Michalis
M
D000818:Animals; D000941:Antigens / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology*; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D015891:Cystatins / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018884:Ixodes / Q000737:chemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000941:Antigens; D015891:Cystatins; D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C515505:sialostatin L, Ixodes scapularis; D002403:Cathepsins; C028217:cathepsin S