The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms.
Helicobacter pylori toxin, VacA, damages the gastric epithelium by erosion and loosening of tight junctions. Here we report that VacA also interferes with T cell activation by two different mechanisms. Formation of anion-specific channels by VacA prevents calcium influx from the extracellular milieu. The transcription factor NF-AT thus fails to translocate to the nucleus and activate key cytokine genes. A second, channel-independent mechanism involves activation of intracellular signaling through the mitogen-activated protein kinases MKK3/6 and p38 and the Rac-specific nucleotide exchange factor, Vav. As a consequence of aberrant Rac activation, disordered actin polymerization is stimulated. The resulting defects in T cell activation may help H. pylori to prevent an effective immune response leading to chronic colonization of its gastric niche.
Boncristiano
Marianna
M
Department of Evolutionary Biology, University of Sienna, 53100 Siena, Italy.
Paccani
Silvia Rossi
SR
Barone
Silvia
S
Ulivieri
Cristina
C
Patrussi
Laura
L
Ilver
Dag
D
Amedei
Amedeo
A
D'Elios
Mario Milco
MM
Telford
John L
JL
Baldari
Cosima T
CT
D021581:Active Transport, Cell Nucleus; D001426:Bacterial Proteins / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D050778:NFATC Transcription Factors; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; C074689:VacA protein, Helicobacter pylori; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium