The Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein, a toll-like receptor 4 agonist, enhances dendritic cell-based cancer vaccine potency.
In this study, we showed the direct interaction between Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein (FAP) and toll-like receptor4 (TLR4) via co-localization and binding by using confocal microscopy and co-immunoprecipitation assays. FAP triggered the expression of pro- and antiinflammatory cytokines in a TLR4-dependent manner. In addition, FAP-induced cytokine expression in bone marrow-derived dendritic cells (BMDCs) was modulated in part by glycogen synthase kinase-3 (GSK-3). FAP-induced expression of CD80, CD86, major histocompatibility complex (MHC) class I, and MHC class II in TLR4(+/+) BMDCs was not observed in TLR4(-/-) BMDCs. Furthermore, FAP induced DC-mediated CD8(+) T cell proliferation and cytotoxic T lymphocyte (CTL) activity, and suppressed tumor growth with DC-based tumor vaccination in EG7 thymoma murine model. Taken together, these results indicate that the TLR4 agonist, FAP, a potential immunoadjuvant for DC-based cancer vaccination, improves the DC-based immune response via the TLR4 signaling pathway.
Department of Microbiology and Immunology, School of Medicine, Pusan National University, Yangsan 626-870, Korea    Research Institute of Convergence of Biomedical Science and Technology, Pusan National University, Yangsan 626-770, Korea.
Kyung Tae
KT
Noh
Sung Jae
SJ
Shin
Kwang Hee
KH
Son
In Duk
ID
Jung
Hyun Kyu
HK
Kang
Su Jung
SJ
Lee
Eun Kyung
EK
Lee
Yong Kyoo
YK
Shin
Ji Chang
JC
You
Yeong-Min
YM
Park
D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines / Q000627:therapeutic use; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009162:Mycobacterium avium / Q000235:genetics / Q000378:metabolism; D010283:Paratuberculosis / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013945:Thymoma / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism
D018829:Adhesins, Bacterial; D019496:Cancer Vaccines; D016207:Cytokines; C117704:FAP-A protein, Mycobacterium avium; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D038362:Glycogen Synthase Kinase 3