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Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA.

Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, Montecucco C - J. Exp. Med. (1998)

Bottom Line: Its role in the chronic infection established by H. pylori is unknown.We found that VacA interferes with proteolytic processing of tetanus toxin and toxoid and specifically inhibits the Ii-dependent pathway of antigen presentation mediated by newly synthesized major histocompatibility complex (MHC) class II, while leaving unaffected the presentation pathway dependent on recycling MHC class II.The results presented here suggest that VacA may contribute to the persistence of H. pylori by interfering with protective immunity and that this toxin is a new useful tool in the study of the different pathways of antigen presentation.

View Article: PubMed Central - PubMed

Affiliation: Centro CNR Biomembrane and Dipartimento di Scienze Biomediche, Università di Padova, 35121 Padova, Italy.

ABSTRACT
A major virulence factor in the stomach chronic infection by Helicobacter pylori is a protein toxin (VacA), which alters cell membrane trafficking of late endosomal/prelysosomal compartments. Its role in the chronic infection established by H. pylori is unknown. To test the possibility that VacA alters antigen processing taking place in prelysosomal compartments, we have used the well-established model of antigen processing and presentation consisting of tetanus toxoid-specific human (CD4(+)) T cells stimulated by autologous antigen-pulsed Epstein-Barr virus-transformed B cells. We found that VacA interferes with proteolytic processing of tetanus toxin and toxoid and specifically inhibits the Ii-dependent pathway of antigen presentation mediated by newly synthesized major histocompatibility complex (MHC) class II, while leaving unaffected the presentation pathway dependent on recycling MHC class II. The results presented here suggest that VacA may contribute to the persistence of H. pylori by interfering with protective immunity and that this toxin is a new useful tool in the study of the different pathways of antigen presentation.

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VacA does not influence NK cell–mediated cytotoxicity. Two NK cell clones  (NK1 and NK2) were tested for  their cytotoxic activity on a mutant EBV-transformed cell line  not expressing HLA class I molecules. The radioactivity released  in the culture medium after 4 h  of incubation at different E/T  ratios is plotted in the figure.  The experiment reported is representative of a set of three different experiments.
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Figure 3: VacA does not influence NK cell–mediated cytotoxicity. Two NK cell clones (NK1 and NK2) were tested for their cytotoxic activity on a mutant EBV-transformed cell line not expressing HLA class I molecules. The radioactivity released in the culture medium after 4 h of incubation at different E/T ratios is plotted in the figure. The experiment reported is representative of a set of three different experiments.

Mentions: Loading of T epitopes on newly synthesized MHC class II molecules is followed by migration and exocytosis of the complexes to the cell surface. In principle this can occur via different intracellular trafficking pathways, such as direct exocytosis of the antigen processing compartment, as suggested by recent evidence (27) or migration to the trans Golgi network followed by exocytosis or recycling to early endosomal compartments. However, knockout of early endosomes does not affect EBV-B cell presentation of TT epitopes to specific T cells (11) and VacA does not interfere with the movement of newly synthesized proteins from the endoplasmic reticulum to the surface in HeLa cells (8). Substantial similarities are apparent between surface expression of MHC class II molecules and the exocytosis of perforin containing granules of NK cells (27, 28). NK cells play a major role in the killing of MHC class I–negative tumor cells (29) and H. pylori prolonged infection increases the probability of development of stomach cancers. These considerations prompted us to investigate the effect of VacA on NK cell cytotoxicity. Fig. 3 shows that the toxin does not inhibit such a process. Together with previous evidence that VacA affects a restricted and late segment of the endocytic pathway (6), these results make it unlikely that VacA inhibits T cell proliferation by interfering with the movement of the antigen–MHC class II complex from the assembly compartment to the cell surface.


Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA.

Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, Montecucco C - J. Exp. Med. (1998)

VacA does not influence NK cell–mediated cytotoxicity. Two NK cell clones  (NK1 and NK2) were tested for  their cytotoxic activity on a mutant EBV-transformed cell line  not expressing HLA class I molecules. The radioactivity released  in the culture medium after 4 h  of incubation at different E/T  ratios is plotted in the figure.  The experiment reported is representative of a set of three different experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199184&req=5

Figure 3: VacA does not influence NK cell–mediated cytotoxicity. Two NK cell clones (NK1 and NK2) were tested for their cytotoxic activity on a mutant EBV-transformed cell line not expressing HLA class I molecules. The radioactivity released in the culture medium after 4 h of incubation at different E/T ratios is plotted in the figure. The experiment reported is representative of a set of three different experiments.
Mentions: Loading of T epitopes on newly synthesized MHC class II molecules is followed by migration and exocytosis of the complexes to the cell surface. In principle this can occur via different intracellular trafficking pathways, such as direct exocytosis of the antigen processing compartment, as suggested by recent evidence (27) or migration to the trans Golgi network followed by exocytosis or recycling to early endosomal compartments. However, knockout of early endosomes does not affect EBV-B cell presentation of TT epitopes to specific T cells (11) and VacA does not interfere with the movement of newly synthesized proteins from the endoplasmic reticulum to the surface in HeLa cells (8). Substantial similarities are apparent between surface expression of MHC class II molecules and the exocytosis of perforin containing granules of NK cells (27, 28). NK cells play a major role in the killing of MHC class I–negative tumor cells (29) and H. pylori prolonged infection increases the probability of development of stomach cancers. These considerations prompted us to investigate the effect of VacA on NK cell cytotoxicity. Fig. 3 shows that the toxin does not inhibit such a process. Together with previous evidence that VacA affects a restricted and late segment of the endocytic pathway (6), these results make it unlikely that VacA inhibits T cell proliferation by interfering with the movement of the antigen–MHC class II complex from the assembly compartment to the cell surface.

Bottom Line: Its role in the chronic infection established by H. pylori is unknown.We found that VacA interferes with proteolytic processing of tetanus toxin and toxoid and specifically inhibits the Ii-dependent pathway of antigen presentation mediated by newly synthesized major histocompatibility complex (MHC) class II, while leaving unaffected the presentation pathway dependent on recycling MHC class II.The results presented here suggest that VacA may contribute to the persistence of H. pylori by interfering with protective immunity and that this toxin is a new useful tool in the study of the different pathways of antigen presentation.

View Article: PubMed Central - PubMed

Affiliation: Centro CNR Biomembrane and Dipartimento di Scienze Biomediche, Università di Padova, 35121 Padova, Italy.

ABSTRACT
A major virulence factor in the stomach chronic infection by Helicobacter pylori is a protein toxin (VacA), which alters cell membrane trafficking of late endosomal/prelysosomal compartments. Its role in the chronic infection established by H. pylori is unknown. To test the possibility that VacA alters antigen processing taking place in prelysosomal compartments, we have used the well-established model of antigen processing and presentation consisting of tetanus toxoid-specific human (CD4(+)) T cells stimulated by autologous antigen-pulsed Epstein-Barr virus-transformed B cells. We found that VacA interferes with proteolytic processing of tetanus toxin and toxoid and specifically inhibits the Ii-dependent pathway of antigen presentation mediated by newly synthesized major histocompatibility complex (MHC) class II, while leaving unaffected the presentation pathway dependent on recycling MHC class II. The results presented here suggest that VacA may contribute to the persistence of H. pylori by interfering with protective immunity and that this toxin is a new useful tool in the study of the different pathways of antigen presentation.

Show MeSH
Related in: MedlinePlus