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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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Effect of VacA on processing and presentation of different T  cell epitopes. T cell clones specific for TT-derived peptides were stimulated with autologous EBV-B cells preincubated for 4 h with 100 nM  VacA or mock-treated and then pulsed with TT. (a) Inhibition by VacA  of the antigen presentation to T cell clones ALT210 and ALT172, which  recognize epitopes that have been generated in late endocytic compartments and loaded onto newly synthesized MHC class II. Overlapping results were obtained with clones ALT81 and KSMix140 (data not shown)  and with the clone KSMix98 as shown in the left of c. (b) Lack of effect of  VacA on the B cell–induced proliferation of T cell clones ALT15 and  ALT220, whose receptors recognize antigen–MHC class II complexes,  which assemble in a recycling compartment independently from de novo  protein synthesis. (c) Left, inhibition by VacA of the presentation to T cell  clone KSMix98; right, the inhibition is circumvented by addition of the  KSMix98-specific T cell epitope P2.
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Figure 2: Effect of VacA on processing and presentation of different T cell epitopes. T cell clones specific for TT-derived peptides were stimulated with autologous EBV-B cells preincubated for 4 h with 100 nM VacA or mock-treated and then pulsed with TT. (a) Inhibition by VacA of the antigen presentation to T cell clones ALT210 and ALT172, which recognize epitopes that have been generated in late endocytic compartments and loaded onto newly synthesized MHC class II. Overlapping results were obtained with clones ALT81 and KSMix140 (data not shown) and with the clone KSMix98 as shown in the left of c. (b) Lack of effect of VacA on the B cell–induced proliferation of T cell clones ALT15 and ALT220, whose receptors recognize antigen–MHC class II complexes, which assemble in a recycling compartment independently from de novo protein synthesis. (c) Left, inhibition by VacA of the presentation to T cell clone KSMix98; right, the inhibition is circumvented by addition of the KSMix98-specific T cell epitope P2.

Mentions: T cell clones specific for TT-derived peptides (ALT15 [epitope P30], ALT81 [P7], ALT172 [P3], ALT210 [C-fragment], ALT220 [P30, from donor A.L.], and KSMix98 and KSMix140 [P2, from donor K.S.]) were stimulated with autologous EBV-B cells preincubated with 100 nM VacA and then pulsed with TT (see Fig. 2, a–c) or with the KSMix98 epitope P2, whose sequence is QYIKANSKFIGITE (see Fig. 2 c). Control EBV-B cells were mock treated. The overnight incorporation of [3H]thymidine in T cells was determined after 48 h of proliferation.


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)

Effect of VacA on processing and presentation of different T  cell epitopes. T cell clones specific for TT-derived peptides were stimulated with autologous EBV-B cells preincubated for 4 h with 100 nM  VacA or mock-treated and then pulsed with TT. (a) Inhibition by VacA  of the antigen presentation to T cell clones ALT210 and ALT172, which  recognize epitopes that have been generated in late endocytic compartments and loaded onto newly synthesized MHC class II. Overlapping results were obtained with clones ALT81 and KSMix140 (data not shown)  and with the clone KSMix98 as shown in the left of c. (b) Lack of effect of  VacA on the B cell–induced proliferation of T cell clones ALT15 and  ALT220, whose receptors recognize antigen–MHC class II complexes,  which assemble in a recycling compartment independently from de novo  protein synthesis. (c) Left, inhibition by VacA of the presentation to T cell  clone KSMix98; right, the inhibition is circumvented by addition of the  KSMix98-specific T cell epitope P2.
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Figure 2: Effect of VacA on processing and presentation of different T cell epitopes. T cell clones specific for TT-derived peptides were stimulated with autologous EBV-B cells preincubated for 4 h with 100 nM VacA or mock-treated and then pulsed with TT. (a) Inhibition by VacA of the antigen presentation to T cell clones ALT210 and ALT172, which recognize epitopes that have been generated in late endocytic compartments and loaded onto newly synthesized MHC class II. Overlapping results were obtained with clones ALT81 and KSMix140 (data not shown) and with the clone KSMix98 as shown in the left of c. (b) Lack of effect of VacA on the B cell–induced proliferation of T cell clones ALT15 and ALT220, whose receptors recognize antigen–MHC class II complexes, which assemble in a recycling compartment independently from de novo protein synthesis. (c) Left, inhibition by VacA of the presentation to T cell clone KSMix98; right, the inhibition is circumvented by addition of the KSMix98-specific T cell epitope P2.
Mentions: T cell clones specific for TT-derived peptides (ALT15 [epitope P30], ALT81 [P7], ALT172 [P3], ALT210 [C-fragment], ALT220 [P30, from donor A.L.], and KSMix98 and KSMix140 [P2, from donor K.S.]) were stimulated with autologous EBV-B cells preincubated with 100 nM VacA and then pulsed with TT (see Fig. 2, a–c) or with the KSMix98 epitope P2, whose sequence is QYIKANSKFIGITE (see Fig. 2 c). Control EBV-B cells were mock treated. The overnight incorporation of [3H]thymidine in T cells was determined after 48 h of proliferation.

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