title: Intradermal administration of the Type II heat-labile enterotoxins LT-IIb and LT-IIc of enterotoxigenic Escherichia coli enhances humoral and CD8+ T cell immunity to a co-administered antigen.
abstract: Vaccinations are extremely effective at combating infectious diseases. Many conserved antigen (Ag) targets, however, are poorly immunogenic. Protein subunit vaccines frequently elicit only humoral immune responses and fail to confer protection against serious intracellular pathogens. These barriers to vaccine development are often overcome by the use of appropriate adjuvants. Heat-labile enterotoxins (HLT) produced by enterotoxigenic strains of Escherichia coli are potent adjuvants when administered by mucosal or systemic routes. The efficacy of the type II HLT, however, has not been well-defined when administered by the intradermal (ID) route. Using a murine ID immunization model, the adjuvant properties of LT-IIb and LT-IIc, two type II HLTs, were compared with those of LT-I, a prototypical type I HLT. While all three HLT adjuvants enhanced Ag-specific humoral responses to similar levels, LT-IIb and LT-IIc, in contrast to LT-I, induced a more vigorous Ag-specific CD8+ T cell response and proffered faster clearance of Listeria monocytogenes in a challenge model. Additionally, LT-IIb and LT-IIc induced distinct differences in the profiles of the Ag-specific CD8+ T cell responses. While LT-IIc stimulated a robust and rapid primary CD8+ T cell response, LT-IIb exhibited slower CD8+ T cell expansion and contraction kinetics with the formation of higher percentages of effector memory cells. In comparison to LT-I and LT-IIc, LT-IIb evoked better long-term protection after immunization. Furthermore, LT-IIb and LT-IIc enhanced the total number of dendritic cells (DC) in the draining lymph node (DLN) and expression of costimulatory molecules CD80, CD86, and CD40 on DCs. In contrast to LT-I, LT-IIb and LT-IIc induced less edema, cellular infiltrates, and general inflammation at the site of ID injection. Thus, LT-IIb and LT-IIc are attractive comprehensive ID adjuvants with unique characteristic that enhance humoral and cellular immunity to a co-administered protein Ag.
authors.affiliation: Department of Microbiology & Immunology and The Witebsky Center for Microbial Pathogenesis and Immunology, The University at Buffalo, Buffalo, New York, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Hu
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Camila
authors.initials: C
authors.lastname: Mathias-Santos
authors.affiliation: Department of Microbiology & Immunology and The Witebsky Center for Microbial Pathogenesis and Immunology, The University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Greene
authors.affiliation: Department of Microbiology & Immunology and The Witebsky Center for Microbial Pathogenesis and Immunology, The University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Natalie D
authors.initials: ND
authors.lastname: King-Lyons
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Juliana F
authors.initials: JF
authors.lastname: Rodrigues
authors.affiliation: University of Pennsylvania School of Dental Medicine, Department of Microbiology, Philadelphia, Pennsylvania, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Luís C S
authors.initials: LC
authors.lastname: Ferreira
authors.affiliation: Department of Microbiology & Immunology and The Witebsky Center for Microbial Pathogenesis and Immunology, The University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Connell
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage* / Q000494:pharmacology; D001427:Bacterial Toxins / Q000008:administration & dosage* / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D054307:Enterotoxigenic Escherichia coli / Q000737:chemistry*; D004768:Enterotoxins / Q000008:administration & dosage* / Q000494:pharmacology*; D029968:Escherichia coli Proteins / Q000008:administration & dosage* / Q000494:pharmacology*; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects*; D056724:Immunity, Humoral / Q000187:drug effects*; D007114:Immunization; D007156:Immunologic Memory / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007271:Injections, Intradermal; D007700:Kinetics; D008089:Listeria monocytogenes / Q000187:drug effects / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D010047:Ovalbumin / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D010047:Ovalbumin; C027538:heat-labile enterotoxin, E coli