Direct inhibition of T-lymphocyte activation by anthrax toxins in vivo

Jason Comer, Ashok Chopra, Johnny Peterson, Rolf König

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8275-8281
Number of pages7
JournalInfection and Immunity
Volume73
Issue number12
DOIs
StatePublished - Dec 2005

Fingerprint

Lymphocyte Activation
T-Lymphocytes
Edema
T-Cell Antigen Receptor
Phosphotransferases
Anthrax Vaccines
Phosphorylation
Capital Punishment
Lymphocytes
Cytokines
Glycogen Synthase Kinase 3
Immune Evasion
Bacillus anthracis
Anthrax
Injections
Macrophage Activation
Protein-Serine-Threonine Kinases
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Immunologic Factors

ASJC Scopus subject areas

  • Immunology

Cite this

Direct inhibition of T-lymphocyte activation by anthrax toxins in vivo. / Comer, Jason; Chopra, Ashok; Peterson, Johnny; König, Rolf.

In: Infection and Immunity, Vol. 73, No. 12, 12.2005, p. 8275-8281.

Research output: Contribution to journalArticle

@article{de54ac4677204c8b9a6e8ccb8094331b,
title = "Direct inhibition of T-lymphocyte activation by anthrax toxins in vivo",
abstract = "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.",
author = "Jason Comer and Ashok Chopra and Johnny Peterson and Rolf K{\"o}nig",
year = "2005",
month = "12",
doi = "10.1128/IAI.73.12.8275-8281.2005",
language = "English",
volume = "73",
pages = "8275--8281",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "12",

}

TY - JOUR

T1 - Direct inhibition of T-lymphocyte activation by anthrax toxins in vivo

AU - Comer, Jason

AU - Chopra, Ashok

AU - Peterson, Johnny

AU - König, Rolf

PY - 2005/12

Y1 - 2005/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=28444498350&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=28444498350&partnerID=8YFLogxK

U2 - 10.1128/IAI.73.12.8275-8281.2005

DO - 10.1128/IAI.73.12.8275-8281.2005

M3 - Article

VL - 73

SP - 8275

EP - 8281

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 12

ER -