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 CD3ζ 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.

Prostaglandin E2, an Immunoactivator

“…This differential action of PGE 2 on Th1 and Th2 cells has been confirmed by many studies (10,11). Because the best known action of PGE 2 at that time was elevation of intracellular cAMP, and cAMP exerted similar Th1-selective suppression (12,13), most, if not all, studies assigned PGE 2 as a modulator of T cells raising the intracellular cAMP level. Among the four subtypes of PGE receptor, EP2 and EP4 are coupled to a rise in cAMP (14).…”

Role of CD11b/CD18 in the Process of Intoxication by the Adenylate Cyclase Toxin of Bordetella pertussis

“…We have demonstrated that polarized epithelial cells respond to Ͻ15 ng/ml of ACT with chloride efflux into the luminal space (11). In addition, IL-2 secretion from activated T cells and T-cell proliferation are impaired by 23 and 46 ng/ml of ACT, respectively (47,50). Interestingly, Paccani et al have recently shown that ACT interacts with LFA-1, another ␤2 integrin, on T cells, and this may account for their sensitivity to ACT (48).…”

“…ACT elicits additional cAMP-mediated effects in a variety of eukaryotic cells; these include apoptotic cell death, dysfunction of the cell cytoskeleton, cell cycle arrest, chloride secretion from polarized epithelial cells, and dysregulation of the adaptive immune system (8,11,22,30,34,47,49,50,54). To generate cAMP, the AC enzyme reaction consumes cellular ATP, further contributing to toxin-mediated cytotoxicity (4, 28).…”

TheBordetella pertussisadenylate cyclase toxin binds to T cells via LFA-1 and induces its disengagement from the immune synapse

“…CyaA triggers the sustained elevation of intracellular Ca 2+ through cAMP-dependent, L-type Ca 2+ channels (Fiser et al, 2007;Martín et al, 2010). The suppressive activities of CyaA on immune cells have been largely ascribed to its capacity to increase intracellular cAMP (Cheung et al, 2008;Paccani et al, 2008;Rossi Paccani et al, 2009;Martín et al, 2010), which acts as a potent immunosuppressant by interfering with the signaling pathways initiated by immunoreceptors (Taskén and Stokka, 2006).…”