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T-cell responses to...
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Lundgren, Anna,1974Gothenburg University,Göteborgs universitet,Institutionen för medicinsk mikrobiologi och immunologi,Institute of Medical Microbiology/Immunology
(författare)
T-cell responses to Helicobacter pylori in humans and a possible role of regulatory T cells
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Nummerbeteckningar
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LIBRIS-ID:oai:gup.ub.gu.se/116048
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ISBN:9162859560
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https://gup.ub.gu.se/publication/116048URI
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Helicobacter pylori colonize the stomach and areas of gastric metaplasia in the duodenum. The bacteria induce both local and systemic immune responses, but despite this, the infection normally persists for life and causes chronic gastritis in all infected subjects and peptic ulcers or gastric cancer in 10-20% of infected individuals. T cells are important components of H. pylori-induced immune responses, but fail to clear the infection. The aim of this thesis was to characterize systemic and mucosal T-cell responses to H. pylori in humans, with focus on regulatory mechanisms. To enable these studies, several methods were developed to optimize isolation of mucosal lymphocytes, to promote antigen specific mucosal T-cell proliferation and to analyse gene expression in small numbers of highly purified T cells.Using these methods, we could demonstrate that stomach mucosa of H. pylori-infected (Hp+) individuals contained higher numbers of CD4+ lamina propria T cells, with increased expression of the homing receptor L-selectin and the chemokine receptor CCR4, than corresponding mucosa from uninfected (Hp-) subjects. Mucosal T-cell proliferation could be promoted by addition of IL-2 and IL-7 and using this technique, H. pylori-specific T-cell proliferation was detected among CD4+ stomach cells from Hp+, but not from Hp- individuals. In contrast, duodenal cells from most individuals responded poorly to stimulation with H. pylori antigens. Furthermore, the duodenum of Hp+ and Hp- individuals contained comparable numbers of T cells with similar receptor expression. These results suggest that most H. pylori-specific CD4+ T cells home to and accumulate in the stomach, possibly with the aid of L-selectin and CCR4 expression. Stimulation of monocyte-derived dendritic cells (DC) with H. pylori bacteria or antigens induced maturation and ability of the DC to migrate towards the chemokine MIP-3â (CCL19), which is expressed in lymph nodes. The stimulation also induced secretion of IL-12 and other proinflammatory cytokines, but little IL-10. These results suggest that DC contribute to the induction and Th1 polarization of T-cell responses to H. pylori.Our studies further demonstrate that the H. pylori-induced T-cell responses are suppressed by regulatory T cells. Blood CD4+ memory T cells from Hp+ individuals responded less to stimulation with H. pylori antigens than cells from Hp- subjects. The responsiveness in cells from Hp+ individuals could be increased by depletion of CD4+CD25high regulatory T cells or addition of IL-2. Furthermore, CD4+CD25high cells directly suppressed H. pylori-induced effector-cell responses in a coculture system. Gastric and duodenal mucosa from Hp+ asymptomatic individuals and duodenal ulcer patients contained increased frequencies of CD4+CD25high T cells compared to mucosa from Hp- individuals. The frequencies of these cells were also increased in the stomach of Hp+ patients with gastric adenocarcinoma and particularly in cancer-affected tissue. CD4+CD25high cells isolated from mucosa of Hp+ individuals expressed Foxp3, a key regulatory gene for Treg function, supporting the Treg identity of these cells. In conclusion, our results show that H. pylori infection induces both mucosal and systemic CD4+ T-cell responses in humans, but that Treg may suppress the responses and thus contribute to the chronicity of H. pylori infection.
Ämnesord och genrebeteckningar
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Helicobacter pylori
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mucosal immunology
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stomach
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duodenum
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asymptomatic
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duodenal ulcer
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gastric adenocarcinoma
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T cells
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regulatory T cells
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dendritic cells
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T-cell recruitment
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Göteborgs universitetInstitutionen för medicinsk mikrobiologi och immunologi
(creator_code:org_t)
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