Helicobacter pylori Type 4 Secretion System Modulates Host T Cell Responses
| dc.contributor.advisor | Reyes, Victor E | |
| dc.contributor.committeeMember | Torres, Alfredo G. | |
| dc.contributor.committeeMember | Pinchuk, Iryna V. | |
| dc.contributor.committeeMember | Bao , Xiaoyong | |
| dc.contributor.committeeMember | Beswick, Ellen J. | |
| dc.creator | Lina, Taslima Taher | |
| dc.date.accessioned | 2016-05-05T21:53:40Z | |
| dc.date.available | 2016-05-05T21:53:40Z | |
| dc.date.created | 2014-08 | |
| dc.date.submitted | August 2014 | |
| dc.date.updated | 2016-05-05T21:53:40Z | |
| dc.description.abstract | Infection with Helicobacter pylori (H. pylori) bacteria is associated with gastritis, peptic ulcer, and gastric cancer. During H. pylori infection CD4+ T cells in the gastric lamina propria are hyporesponsive and polarized to Th1/Th17 cell responses controlled by Treg cells. Gastric epithelial cells (GECs) are the primary target for H. pylori infection and may act as antigen-presenting cells (APCs) regulating local T cell responses. Previously our lab showed that H. pylori up-regulates B7-H1 (a T cell co-inhibitory molecule) expression on GEC, which, in turn, suppress T cell proliferation and effector function, and induce Treg cells in vitro. My studies showed that, along with B7-H1, GEC expresses B7-H2 and B7-H3 molecules. B7-H2 is a T cell co-stimulatory molecule, and B7-H3 has both co-stimulatory and inhibitory functions. Moreover, their expression is modulated during H. pylori infection. In addition, I investigated the underlying mechanisms of these responses-and demonstrated that H. pylori requires its type 4 secretion system (T4SS) translocated components: effector protein CagA and cell-wall peptidoglycan (PG) fragments for up-regulating B7-H1 as well as B7-H3, and for down-regulating B7-H2 on GEC. These data were validated in vivo by using a mouse model of infection. My study demonstrated that, along with T4SS, cytokines produced by Th17 and Treg cells also induce B7-H3 expression. I evaluated the underlying cell signaling pathways and showed that H. pylori uses the p38 MAPK pathway to up-regulate B7-H1 and B7-H3 expression and the p70S6/mTOR pathway for B7-H2 down-regulation in GEC. By using in vitro and in vivo systems, I demonstrated that H. pylori T4SS-mediated up-regulation of B7-H1 expression by GEC caused Treg cell induction and increased bacterial loads whereas H. pylori CagA-mediated B7-H2 down-regulation in GECs correlated with a decrease in Th17-type responses. Furthermore, the modulation of Th17 responses inversely correlated with the H. pylori colonization levels. Finally, the up-regulation of B7-H3 expression resulted in induction of Th2 cells in vitro and in vivo. In conclusion, these studies revealed some novel regulatory mechanisms employed by H. pylori to influence the type of T cell response that develops in the infected gastric mucosa and help in establishing chronic infection there. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/2152.3/712 | |
| dc.subject | Helicobacter pylori, Type 4 secretion system, CagA, B7-H1, B7-H2, B7-H3, Gastric epithelial cells, Treg cells, Th17 cells | |
| dc.title | Helicobacter pylori Type 4 Secretion System Modulates Host T Cell Responses | |
| dc.type | Thesis | |
| dc.type.material | text | |
| thesis.degree.department | Microbiology and Immunology | |
| thesis.degree.discipline | Immunology | |
| thesis.degree.grantor | The University of Texas Medical Branch at Galveston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Microbiology and Immunology (Doctoral) |