This Article Full Text Full Text (PDF) Other Versions of this Article: IAI.00414-07v1 75/8/4040    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schneider, O. D. Articles by Miller, W. E. Search for Related Content PubMed PubMed Citation Articles by Schneider, O. D. Articles by Miller, W. E.

 Previous Article  |  Next Article 

Infection and Immunity, August 2007, p. 4040-4049, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00414-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Pertussis Toxin Utilizes Proximal Components of the T-Cell Receptor Complex To Initiate Signal Transduction Events in T Cells

Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Received 20 March 2007/ Returned for modification 9 May 2007/ Accepted 29 May 2007

Pertussis toxin (PTx) is an AB₅ toxin produced by the human pathogen Bordetella pertussis. Previous work demonstrates that the five binding (B) subunits of PTx can have profound effects on T lymphocytes independent of the enzymatic activity of the A subunit. Stimulation of T cells with holotoxin (PTx) or the B subunit alone (PTxB) rapidly induces signaling events resulting in inositol phosphate accumulation, Ca²⁺ mobilization, interleukin-2 (IL-2) production, and mitogenic cell growth. Although previous reports suggest the presence of PTx signaling receptors expressed on T cells, to date, the receptor(s) and membrane proximal signaling events utilized by PTx remain unknown. Here we genetically and biochemically define the membrane proximal components utilized by PTx to initiate signal transduction in T cells. Using mutants of the Jurkat T-cell line deficient for key components of the T-cell receptor (TCR) pathway, we have compared stimulation with PTx to that of anti-CD3 monoclonal antibody (MAb), which directly interacts with and activates the TCR complex. Our genetic data in combination with biochemical analysis show that PTx (via the B subunit) activates TCR signaling similar to that of anti-CD3 MAb, including activation of key signaling intermediates such as Lck, ZAP-70, and phospholipase C-1. Moreover, the data indicate that costimulatory activity, as provided by CD28 ligation, is required for PTx to fully stimulate downstream indicators of T-cell activation such as IL-2 gene expression. By illuminating the signaling pathways that PTx activates in T cells, we provide a mechanistic understanding for how these signals deregulate immune system functions during B. pertussis infection.

Published ahead of print on 11 June 2007.

Editor: D. L. Burns