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Infection and Immunity, March 2007, p. 1413-1423, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01367-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro Induction of Immunoglobulin A (IgA)- and IgM-Secreting Plasma Blasts by Cholera Toxin Depends on T-Cell Help and Is Mediated by CD154 Up-Regulation and Inhibition of Gamma Interferon Synthesis

Sergio Arce,^1,2* Hesham F. Nawar,^1,2 Gwendolin Muehlinghaus,⁴ Michael W. Russell,^1,2,3, and Terry D. Connell^1,2,

Department of Microbiology and Immunology,¹ Witebsky Center for Microbial Pathogenesis and Immunology,² Department of Oral Biology, The University at Buffalo, The State University of New York at Buffalo, Buffalo, New York,³ Department of Humoral Immunology, Deutsches Rheumaforschungszentrum, Berlin, Germany⁴

Received 24 August 2006/ Returned for modification 31 October 2006/ Accepted 21 December 2006

Cholera toxin (CT) and the type II heat-labile enterotoxins (LT-IIa and LT-IIb) are potent immunological adjuvants which are hypothesized to enhance the production of antibody (Ab)-secreting cells, although their mechanisms of action are not fully understood. The treatment of splenic cells with concanavalin A (ConA) plus CT enhanced the production of immunoglobulin A (IgA) and IgM by dividing cells that expressed high levels of major histocompatibility complex class II (MHC-II), CD19, and CD138 and low levels of B220 a phenotype characteristic of plasma blasts. LT-IIa or LT-IIb moderately enhanced IgA and IgM production without enhancing plasma blast differentiation. CT up-regulated CD25, CD69, CD80, CD86, and MHC-II in isolated B cells but failed to induce proliferation or differentiation. The treatment of unfractionated splenic cells with ConA plus CT induced B-cell proliferation and differentiation, but the elimination of CD4⁺ T cells inhibited this effect. CT treatment of ConA-activated CD4⁺ T cells up-regulated CD134 and CD154, whereas the blockage of CD40-CD154 interactions inhibited the induction of plasma blasts and Ig synthesis. The treatment of unfractionated splenic cells with CT, LT-IIa, or LT-IIb enhanced the production of interleukin-6 (IL-6) and IL-10, whereas the production of gamma interferon was inhibited in both CD4⁺ and CD8⁺ T cells mostly by CT. Thus, major regulatory effects of CT on lymphocytes are likely exerted early during the induction of immune responses when B and T cells initially encounter antigen. Neither LT-IIa or LT-IIb had these effects, indicating that type II enterotoxins augment Ab responses by other mechanisms.

Published ahead of print on 12 January 2007.

Editor: V. J. DiRita

M.W.R. and T.D.C. are co-senior authors.