title: The adenylate cyclase toxins of Bacillus anthracis and Bordetella pertussis promote Th2 cell development by shaping T cell antigen receptor signaling.
abstract: The adjuvanticity of bacterial adenylate cyclase toxins has been ascribed to their capacity, largely mediated by cAMP, to modulate APC activation, resulting in the expression of Th2-driving cytokines. On the other hand, cAMP has been demonstrated to induce a Th2 bias when present during T cell priming, suggesting that bacterial cAMP elevating toxins may directly affect the Th1/Th2 balance. Here we have investigated the effects on human CD4(+) T cell differentiation of two adenylate cyclase toxins, Bacillus anthracis edema toxin (ET) and Bordetella pertussis CyaA, which differ in structure, mode of cell entry, and subcellular localization. We show that low concentrations of ET and CyaA, but not of their genetically detoxified adenylate cyclase defective counterparts, potently promote Th2 cell differentiation by inducing expression of the master Th2 transcription factors, c-maf and GATA-3. We also present evidence that the Th2-polarizing concentrations of ET and CyaA selectively inhibit TCR-dependent activation of Akt1, which is required for Th1 cell differentiation, while enhancing the activation of two TCR-signaling mediators, Vav1 and p38, implicated in Th2 cell differentiation. This is at variance from the immunosuppressive toxin concentrations, which interfere with the earliest step in TCR signaling, activation of the tyrosine kinase Lck, resulting in impaired CD3zeta phosphorylation and inhibition of TCR coupling to ZAP-70 and Erk activation. These results demonstrate that, notwithstanding their differences in their intracellular localization, which result in focalized cAMP production, both toxins directly affect the Th1/Th2 balance by interfering with the same steps in TCR signaling, and suggest that their adjuvanticity is likely to result from their combined effects on APC and CD4(+) T cells. Furthermore, our results strongly support the key role of cAMP in the adjuvanticity of these toxins.
authors.affiliation: Department of Evolutionary Biology, University of Siena, Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi Paccani
authors.forename: Marisa
authors.initials: M
authors.lastname: Benagiano
authors.forename: Nagaja
authors.initials: N
authors.lastname: Capitani
authors.forename: Irene
authors.initials: I
authors.lastname: Zornetta
authors.forename: Daniel
authors.initials: D
authors.lastname: Ladant
authors.forename: Cesare
authors.initials: C
authors.lastname: Montecucco
authors.forename: Mario M
authors.initials: MM
authors.lastname: D'Elios
authors.forename: Cosima T
authors.initials: CT
authors.lastname: Baldari
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000235:genetics / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000235:genetics / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000201:enzymology* / Q000235:genetics; D001427:Bacterial Toxins / Q000235:genetics / Q000494:pharmacology*; D001886:Bordetella pertussis / Q000201:enzymology* / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018418:Th2 Cells / Q000378:metabolism
chemical_list: D037361:Adenylate Cyclase Toxin; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; D011948:Receptors, Antigen, T-Cell; C030325:anthrax toxin; D000242:Cyclic AMP; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases