Recombinant antigen-enterotoxin A2/B chimeric mucosal immunogens differentially enhance antibody responses and B7-dependent costimulation of CD4(+) T cells.
The ADP-ribosylating enterotoxins, cholera toxin (CT) and the Escherichia coli heat-labile toxin (LT-IIa), have been shown to enhance mucosal and systemic antibody (Ab) responses to coadministered antigens. The purpose of the present study was to compare the ability of the nontoxic A2/B subunits of these toxins, which have distinct targeting properties, to augment the immunogenicity of a genetically coupled protein antigen. Structurally similar chimeric proteins were generated by genetically replacing the toxic A1 subunit of CT or LT-IIa with the saliva-binding region (SBR) from the streptococcal adhesin AgI/II. Intranasal immunization of BALB/c mice with either chimeric protein induced significantly higher plasma and mucosal anti-SBR immunoglobulin A (IgA) and IgG Ab responses than SBR alone. Moreover, compared to SBR-LT-IIaA2/B, SBR-CTA2/B elicited significantly higher levels of plasma IgG1 and salivary IgA anti-SBR Ab responses. Ex vivo and in vitro experiments revealed that SBR-CTA2/B selectively up-regulated B7-2 expression on murine B cells isolated from both the nasal associated lymphoid tissue, cervical lymph nodes, and spleen. In contrast, SBR-LT-IIaA2/B had little effect on B7-1 or B7-2 expression on B220(+), CD11b(+), or CD11c(+) cells. Analysis of the functional costimulatory activity of SBR-CTA2/B-treated B cells revealed a significant enhancement in anti-CD3-stimulated CD4(+) T-cell proliferative responses, and this proliferation was significantly reduced by treatment with anti-B7-2 but not with anti-B7-1 or isotype control Abs. Thus, SBR-CTA2/B and SBR-LT-IIaA2/B exhibit distinct patterns of antibody responses associated with differential effects on B7-2 expression and subsequent costimulatory effects on CD4(+) T cells.
Martin
M
M
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Hajishengallis
G
G
Metzger
D J
DJ
Michalek
S M
SM
Connell
T D
TD
Russell
M W
MW
D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D000938:Antigen-Presenting Cells / Q000502:physiology; D000942:Antigens, Bacterial / Q000276:immunology*; D015703:Antigens, CD / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology*; D051940:B7-2 Antigen; D001427:Bacterial Toxins / Q000276:immunology*; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002772:Cholera Toxin / Q000276:immunology; D004768:Enterotoxins / Q000276:immunology*; D029968:Escherichia coli Proteins; D005260:Female; D007114:Immunization; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000276:immunology*
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D001427:Bacterial Toxins; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli