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Infection and Immunity, July 2001, p. 4486-4492, Vol. 69, No. 7
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.7.4486-4492.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Distinct Cytokine Regulation by Cholera Toxin and Type II Heat-Labile Toxins Involves Differential Regulation of CD40 Ligand on CD4+ T Cells

Michael Martin,1,* 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 352941 and Center for Microbial Pathogenesis and Department of Microbiology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 142142

Received 1 February 2001/Returned for modification 30 March 2001/Accepted 9 April 2001

Cholera toxin (CT) and the type II heat-labile enterotoxins (HLT) LT-IIa and LT-IIb act as potent systemic and mucosal adjuvants and induce distinct T-helper (Th)-cell cytokine profiles. In the present study, CT and the type II HLT were found to differentially affect cytokine production by anti-CD3-stimulated human peripheral blood mononuclear cells (PBMC), and the cellular mechanisms responsible were investigated. CT suppressed interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-alpha ), and IL-12 production by PBMC cultures more than either LT-IIa or LT-IIb. CT but not LT-IIa or LT-IIb reduced the expression of CD4+ T-cell surface activation markers (CD25 and CD69) and subsequent proliferative responses of anti-CD3-stimulated T cells. CT but not LT-IIa or LT-IIb significantly reduced the expression of CD40 ligand (CD40L) on CD4+ T cells. In a coculture system, CT-treated CD4+ T cells induced significantly less TNF-alpha and IL-12 p70 production by both autologous monocytes and monocyte-derived dendritic cells than either LT-IIa- or LT-IIb-treated CD4+ T cells. These findings demonstrate that CT, LT-IIa, and LT-IIb differentially affect CD40-CD40L interactions between antigen-presenting cells and T cells and help explain the distinct cytokine profiles observed with type I and type II HLT when used as mucosal adjuvants.

* Corresponding author. Mailing address: Department of Microbiology, University of Alabama at Birmingham, 845 South 19th, BBRB 634, Birmingham, AL 35294-2170. Phone: (205) 934-3033. Fax: (205) 934-3894. E-mail: michmart{at}uab.edu.

Infection and Immunity, July 2001, p. 4486-4492, Vol. 69, No. 7
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.7.4486-4492.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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