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Infection and Immunity, May 2009, p. 1924-1935, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01559-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cholera Toxin and Escherichia coli Heat-Labile Enterotoxin, but Not Their Nontoxic Counterparts, Improve the Antigen-Presenting Cell Function of Human B Lymphocytes{triangledown}

Donatella R. M. Negri,1* Dora Pinto,1 Silvia Vendetti,1 Mario Patrizio,2 Massimo Sanchez,3 Antonella Riccomi,1 Paolo Ruggiero,4 Giuseppe Del Giudice,4 and Maria Teresa De Magistris1

Department of Infectious, Parasitic and Immune-Mediated Diseases,1 Department of Therapeutic Research and Medicines Evaluation,2 Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy,3 Research Center, Novartis Vaccines, Siena, Italy4

Received 23 December 2008/ Accepted 9 February 2009

B lymphocytes play an important role in the immune response induced by mucosal adjuvants. In this study we investigated the in vitro antigen-presenting cell (APC) properties of human B cells upon treatment with cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) and nontoxic counterparts of these toxins, such as the B subunit of CT (CT-B) and the mutant of LT lacking ADP ribosyltransferase activity (LTK63). Furthermore, forskolin (FSK), a direct activator of adenylate cyclase, and cyclic AMP (cAMP) analogues were used to investigate the role of the increase in intracellular cAMP caused by the A subunit of CT and LT. B lymphocytes were cultured with adjuvants and polyclonal stimuli necessary for activation of B cells in the absence of CD4 T cells. Data indicated that treatment with CT, LT, FSK, or cAMP analogues, but not treatment with CT-B or LTK63, upregulated surface activation markers on B cells, such as CD86 and HLA-DR, and induced inhibition of the proliferation of B cells at early time points, while it increased cell death in long-term cultures. Importantly, B cells treated with CT, LT, or FSK were able to induce pronounced proliferation of both CD4+ and CD8+ allogeneic T cells compared with untreated B cells and B cells treated with CT-B and LTK63. Finally, only treatment with toxins or FSK induced antigen-specific T-cell proliferation in Mycobacterium tuberculosis purified protein derivative or tetanus toxoid responder donors. Taken together, these results indicated that the in vitro effects of CT and LT on human B cells are mediated by cAMP.

* Corresponding author. Mailing address: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Phone: 39-6-49902734. Fax: 39-6-49902886. E-mail: donatella.negri{at}iss.it

{triangledown} Published ahead of print on 17 February 2009.

Editor: S. R. Blanke

Infection and Immunity, May 2009, p. 1924-1935, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01559-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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