title: TLR2-dependent modulation of dendritic cells by LT-IIa-B5, a novel mucosal adjuvant derived from a type II heat-labile enterotoxin.
abstract: A host of human pathogens invades the body at mucosal surfaces. Yet, strong, protective mucosal immune responses directed against those pathogens routinely cannot be induced without the use of adjuvants. Although the strongest mucosal adjuvants are members of the family of HLTs, the inherent toxicities of HLT holotoxins preclude their clinical use. Herein, it is shown that LT-IIa-B(5) enhances mucosal immune responses by modulating activities of DCs. i.n. immunization of mice with OVA in the presence of LT-IIa-B(5) recruited DCs to the NALT and significantly increased uptake of OVA by those DCs. Furthermore, LT-IIa-B(5) increased expression of CCR7 by DCs, which mediated enhanced migration of the cells from the NALT to the draining CLNs. LT-IIa-B(5) also enhanced maturation of DCs, as revealed by increased surface expression of CD40, CD80, and CD86. Ag-specific CD4(+) T cell proliferation was augmented in the CLNs of mice that had received i.n. LT-IIa-B(5). Finally, when used as an i.n. adjuvant, LT-IIa-B(5) dramatically increased the levels of OVA-specific salivary IgA and OVA-specific serum IgG. Strikingly, each of the activities induced by LT-IIa-B(5) was strictly TLR2-dependent. The data strongly suggest that the immunomodulatory properties of LT-IIa-B(5) depend on the productive modulation of mucosal DCs. Notably, this is the first report for any HLT to demonstrate in vivo the elicitation of strong, TLR2-dependent modulatory effects on DCs with respect to adjuvanticity.
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Lee
authors.forename: Patricia
authors.initials: P
authors.lastname: Masso-Welch
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
authors.forename: Terry D
authors.initials: TD
authors.lastname: Connell
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry; D000281:Administration, Intranasal; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D004768:Enterotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D018928:Immunity, Mucosal; D007114:Immunization; D056747:Immunomodulation; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000166:cytology / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D001427:Bacterial Toxins; D019013:CD40 Antigens; D004768:Enterotoxins; D029968:Escherichia coli Proteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D010047:Ovalbumin; C027538:heat-labile enterotoxin, E coli