Bacillus anthracis Lethal Toxin Disrupts TCR Signaling in CD1d-Restricted NKT Cells Leading to Functional Anergy

Abstract

Exogenous CD1d-binding glycolipid (α-Galactosylceramide, α-GC) stimulates TCR signaling and activation of type-1 natural killer–like T (NKT) cells. Activated NKT cells play a central role in the regulation of adaptive and protective immune responses against pathogens and tumors. In the present study, we tested the effect of Bacillus anthracis lethal toxin (LT) on NKT cells both in vivo and in vitro. LT is a binary toxin known to suppress host immune responses during anthrax disease and intoxicates cells by protective antigen (PA)-mediated intracellular delivery of lethal factor (LF), a potent metalloprotease. We observed that NKT cells expressed anthrax toxin receptors (CMG-2 and TEM-8) and bound more PA than other immune cell types. A sub-lethal dose of LT administered in vivo in C57BL/6 mice decreased expression of the activation receptor NKG2D by NKT cells but not by NK cells. The in vivo administration of LT led to decreased TCR-induced cytokine secretion but did not affect TCR expression. Further analysis revealed LT-dependent inhibition of TCR-stimulated MAP kinase signaling in NKT cells attributable to LT cleavage of the MAP kinase kinase MEK-2. We propose that Bacillus anthracis–derived LT causes a novel form of functional anergy in NKT cells and therefore has potential for contributing to immune evasion by the pathogen.

Anthrax Lethal Toxin Impairs CD1d-Mediated Antigen Presentation by Targeting the Extracellular Signal-Related Kinase 1/2 Mitogen-Activated Protein Kinase Pathway

“…1E). Interestingly, MAPKs play an important role in T-cell receptor (TCR)-mediated signaling for optimum T cell activation (37), and anthrax toxin causes functional anergy in NKT cells by disrupting TCR signaling (17). MAPKs also regulate CD1d-mediated antigen presentation by altering the intracellular trafficking and distribution of CD1d (25).…”

Toxin Inhibition of Antimicrobial Factors Induced by Bacillus anthracis Peptidoglycan in Human Blood

“…Although LT and ET have been studied extensively in recent years and both are known to suppress immune responses (9,(14)(15)(16)(17)(18)(19), little is known about the immunomodulatory effects unique to LT or ET. Where differences have been found, LT seems to be the dominant toxin for immunosuppression.…”

“…AT intoxicates many different cell types, and a substantial number of studies have described the immunosuppressive effects of lethal toxin (LT) and edema toxin (ET) (10,13). Both innate and humoral immune responses are crippled by AT, with effects such as blocking cytokine production, reducing neutrophil chemotaxis, altering T and B cell responses, and inducing anergy in NKT cells (9,(14)(15)(16)(17)(18)(19).…”

Quand les cellules iNKT partent au charbon : nouvelles pistes thérapeutiques

“…Plusieurs études ont montré le rôle potentiel de l'alpha-galactosylcéramide (-GalCer), un glycolipide de synthèse, puissant agoniste du récepteur T des cellules iNKT, dans i) l'activation de ces cellules iNKT, ii) la mise en place du contrôle de certaines infections comme les pneumonies à Streptococcus pneumoniae [5], ou iii) pour promouvoir le développement de réponses anti-tumorales et anti-diabétiques [6] (➜). Les cellules iNKT ont également été décrites comme jouant un rôle dans l'orchestration de l'immunité adaptative et la production d'anticorps par les lymphocytes B contre la bactérie Bacillus anthracis, l'agent de la maladie du charbon (ou anthrax pour les anglo-saxons) [7,8]. Cependant, aucune étude ne s'est intéressée au rôle potentiel de l'activation des cellules iNKT par l'-GalCer sur la réponse cellulaire à la suite d'une infection par B. anthracis.…”