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Infection and Immunity, January 2001, p. 252-261, Vol. 69, No. 1
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.1.252-261.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Recombinant Antigen-Enterotoxin A2/B Chimeric Mucosal Immunogens Differentially Enhance Antibody Responses and B7-Dependent Costimulation of CD4+ T Cells

Michael Martin,1,* George Hajishengallis,2 Daniel J. Metzger,2 Suzanne M. Michalek,1 Terry D. Connell,2 and Michael W. Russell1

Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294,1 and Center for Microbial Pathogenesis and the Department of Microbiology School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 142142

Received 6 June 2000/Returned for modification 31 August 2000/Accepted 5 October 2000

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.

* Corresponding author. Mailing address: Department of Microbiology, University of Alabama at Birmingham, 845 South 19th St., BBRB 738, Birmingham, AL 35294-2170. Phone: (205) 934-1233. Fax: (205) 934-3894. E-mail: michmart{at}uab.edu.

Infection and Immunity, January 2001, p. 252-261, Vol. 69, No. 1
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.1.252-261.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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