Listeria monocytogenes induces T cell receptor unresponsiveness through pore-forming toxin listeriolysin O.
BACKGROUND
The success of many pathogens relies on their ability to circumvent the innate and adaptive immune defenses. How bacterial pathogens subvert adaptive immune defenses is not clear. Cholesterol-dependent cytolysins (CDCs) represent an expansive family of homologous pore-forming toxins that are produced by more than 20 gram-positive bacterial species. Listeriolysin O (LLO), a prototype CDC, is the main virulence factor of Listeria monocytogenes.


METHODS
We employed flow cytometric and microarray techniques to analyze the effect of LLO on T cell activation in vitro and in vivo.


RESULTS
In vivo and in vitro proliferation of CD4(+) T cells upon T cell receptor (TCR) activation was highly diminished in the presence of LLO or wild-type L. monocytogenes but not in the presence of LLO-deficient L. monocytogenes. This block in T cell proliferation was specific to T cell activation via the TCR and not by phorbol 12-myristate 13-acetate-ionomycin, which bypasses the proximal TCR signaling event. The results of microarray analysis suggest that LLO-induced T cell unresponsiveness is due to the induction of a calcium-nuclear factor of activated T cells-dependent transcriptional program that drives the expression of negative regulators of TCR signaling.


CONCLUSIONS
These findings provide important insights into how bacterial toxins silence adaptive immune responses and thus enable prolonged survival of the pathogen in the host.
Gekara
Nelson O
NO
Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany. nelson.gekara@mims.umu.se
Zietara
Natalia
N
Geffers
Robert
R
Weiss
Siegfried
S
D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology*; D006460:Hemolysin Proteins / Q000235:genetics / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D011948:Receptors, Antigen, T-Cell / Q000032:analysis*; D013047:Specific Pathogen-Free Organisms
D001427:Bacterial Toxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D011948:Receptors, Antigen, T-Cell; C038705:hlyA protein, Listeria monocytogenes