title: Mycobacterium paratuberculosis CobT activates dendritic cells via engagement of Toll-like receptor 4 resulting in Th1 cell expansion.
abstract: Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne disease in animals and MAP involvement in human Crohn disease has been recently emphasized. Evidence from M. tuberculosis studies suggests mycobacterial proteins activate dendritic cells (DCs) via Toll-like receptor (TLR) 4, eventually determining the fate of immune responses. Here, we investigated whether MAP CobT contributes to the development of T cell immunity through the activation of DCs. MAP CobT recognizes TLR4, and induces DC maturation and activation via the MyD88 and TRIF signaling cascades, which are followed by MAP kinases and NF-κB. We further found that MAP CobT-treated DCs activated naive T cells, effectively polarized CD4(+) and CD8(+) T cells to secrete IFN-γ and IL-2, but not IL-4 and IL-10, and induced T cell proliferation. These data indicate that MAP CobT contributes to T helper (Th) 1 polarization of the immune response. MAP CobT-treated DCs specifically induced the expansion of CD4(+)/CD8(+)CD44(high)CD62L(low) memory T cells in the mesenteric lymph node of MAP-infected mice in a TLR4-dependent manner. Our results indicate that MAP CobT is a novel DC maturation-inducing antigen that drives Th1 polarized-naive/memory T cell expansion in a TLR4-dependent cascade, suggesting that MAP CobT potentially links innate and adaptive immunity against MAP.
authors.affiliation: Department of Microbiology and Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Eui-Hong
authors.initials: EH
authors.lastname: Byun
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Kim
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Kim
authors.forename: Choul-Jae
authors.initials: CJ
authors.lastname: Won
authors.forename: Han-Gyu
authors.initials: HG
authors.lastname: Choi
authors.forename: Hwa-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.forename: Keehoon
authors.initials: K
authors.lastname: Lee
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zhang
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D007107:Immune System; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000235:genetics* / Q000502:physiology; D016927:Mycobacterium avium subsp. paratuberculosis / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000235:genetics* / Q000502:physiology; D010430:Pentosyltransferases / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; D010430:Pentosyltransferases; C028015:nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferase; D009713:Nucleotidyltransferases