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Infection and Immunity, December 2005, p. 8275-8281, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8275-8281.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Direct Inhibition of T-Lymphocyte Activation by Anthrax Toxins In Vivo

Jason E. Comer,1 Ashok K. Chopra,2 Johnny W. Peterson,2 and Rolf König2,3*

Departments of Experimental Pathology,1 Microbiology and Immunology,2 Sealy Center for Molecular Science, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-10703

Received 28 June 2005/ Returned for modification 4 September 2005/ Accepted 18 September 2005

The causative agent of anthrax, Bacillus anthracis, produces two toxins that contribute in part to its virulence. Lethal toxin is a metalloprotease that cleaves upstream mitogen-activated protein kinase kinases. Edema toxin is a calmodulin-dependent adenylate cyclase. Previous studies demonstrated that the anthrax toxins are important immunomodulators that promote immune evasion of the bacterium by suppressing activation of macrophages and dendritic cells. Here we showed that injection of sublethal doses of either lethal or edema toxin into mice directly inhibited the subsequent activation of T lymphocytes by T-cell receptor-mediated stimulation. Lymphocytes were isolated from toxin-injected mice after 1 or 4 days and stimulated with antibodies against CD3 and CD28. Treatment with either toxin inhibited the proliferation of T cells. Injection of lethal toxin also potently inhibited cytokine secretion by stimulated T cells. The effects of edema toxin on cytokine secretion were more complex and were dependent on the length of time between the injection of edema toxin and the isolation of lymphocytes. Treatment with lethal toxin blocked multiple kinase signaling pathways important for T-cell receptor-mediated activation of T cells. Phosphorylation of the extracellular signal-regulated kinase and the stress-activated kinase p38 was significantly decreased. In addition, phosphorylation of the serine/threonine kinase AKT and of glycogen synthase kinase 3 was inhibited in T cells from lethal toxin-injected mice. Thus, anthrax toxins directly act on T lymphocytes in a mouse model. These findings are important for future anthrax vaccine development and treatment.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070. Phone: (409) 747-0395. Fax: (409) 747-6869. E-mail: rokonig{at}utmb.edu.

Editor: J. D. Clements

Infection and Immunity, December 2005, p. 8275-8281, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8275-8281.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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