Helicobacter pylori chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear H. pylori infections is a consequence of active suppression of the immune response. Here we show that H. pylori-infected individuals have increased frequencies of CD4؉ CD25 high T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express The gastrointestinal mucosa is in constant contact with both harmless and harmful antigens. The immune system has to discriminate between these antigens to maintain a balance between active defense and the prevention of immunopathology. In mouse models, naturally occurring CD4 ϩ CD25 ϩ regulatory T cells (T reg cells) have been implicated in playing an important role in suppressing immune responses to the normal intestinal flora (28) as well as to pathogens (22,25). However, little is currently known about the role of T reg cells in the human gastrointestinal mucosa.Most studies of human T reg cells have been performed with cells isolated from peripheral blood (2, 17, 32), but CD4 ϩ CD25ϩ cells with suppressor activity have also been demonstrated in the thymus (29), cord blood (36), synovial fluid (4), tonsils (32), and a few types of tumors (19,37). Human T cells have a more variable expression of CD25 (the interleukin-2 receptor ␣-chain) than do mouse T cells, and only those that express CD25 with the highest intensities (CD25 high ) are suppressive (2, 4). T cells expressing intermediate levels of CD25 (CD25 low ) are instead activated effector or memory T cells and lack a regulatory function. T reg cells suppress the activity of other T cells via a contact-dependent mechanism, but the molecules directly mediating this suppression have still not been clearly identified (22). However, the Foxp3 gene (FOXP3 in humans), which encodes the transcription factor scurfin, has recently been demonstrated to be a key regulatory gene for the development and function of T reg cells (10,15,16). Humans with defects in the FOXP3 gene experience strong activation of the immune system, leading to multiorgan autoimmune disease, inflammatory bowel disease, allergies, and severe infections, collectively known as the IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance syndrome) (11). FOXP3/Foxp3 is expressed by CD4 ϩ CD25ϩ T reg cells in humans and mice, and the transduction of CD25 Ϫ cells from mice with this gene converts the cells into regulatory cells. Although recent data indicate that FOXP3 gene expression can be induced in CD25Ϫ cells under special conditions (5, 9, 33, 34), these induced FOXP3-expressing cells also have a suppressive capacity, suggesting that a tight link exists between FOXP3 expression and a regulatory function.We are currently investigating the role of T reg cells in chronic Helicobacter pylori infection (20,25). Although H. pylori colo...

Helicobacter pylori colonizes the gastric and duodenal mucosa. The infection normally persists for life and causes peptic ulcers and gastric cancer in a subset of infected individuals. We hypothesized that the inability to clear the infection may be a consequence of H. pylori-specific regulatory T cells that actively suppress T-cell responses. Therefore, we characterized the T-cell responses to H. pylori in H. pylori-infected individuals without any subjective symptoms and in uninfected control subjects and investigated the role of regulatory CD4

No abstract

Continuous recruitment of neutrophils into the inflamed gastric mucosal tissue is a hallmark of Helicobacter pylori infection in humans. In this study, we examined the ability of H. pylori to induce transendothelial migration of neutrophils using a transwell system consisting of a cultured monolayer of human endothelial cells as barrier between two chambers. We showed for the first time that live H. pylori, but not formalin-killed bacteria, induced a significantly increased transendothelial migration of neutrophils. H. pylori conditioned culture medium also induced significantly increased transendothelial migration, whereas heat-inactivated culture filtrates had no effect, suggesting that the chemotactic factor was proteinaceous. Depletion of H. pylori-neutrophil activating protein (HP-NAP) from the culture filtrates resulted in significant reduction of the transmigration. Culture filtrates from isogenic HP-NAP deficient mutant bacteria also induced significantly less neutrophil migration than culture filtrates obtained from wild-type bacteria. HP-NAP did not induce endothelial cell activation, suggesting that HP-NAP acts directly on the neutrophils. In conclusion, our results demonstrate that secreted HP-NAP is one of the factors resulting in H. pylori induced neutrophil transendothelial migration. We propose that HP-NAP contributes to the continuous recruitment of neutrophils to the gastric mucosa of H. pylori infected individuals.

Cell-mediated immunity is thought to be the main mechanism of anti-tumour responses of the host, but it is not known if cancer disease affects T cell recruitment from blood to tissues. Therefore, we compared Heliobacter pylori-induced T cell transendothelial migration (TEM) in H. pylori-infected gastric carcinoma patients, colon and lung carcinoma patients and healthy volunteers. H. pylori induced significant T cell migration from all groups. However, there was a dramatic reduction of T cell TEM in gastric carcinoma patients (80%) compared to healthy individuals. A similarly reduced transmigration was also seen in colon and lung carcinoma patients. We found significantly increased frequencies of T reg cells in the blood of gastric carcinoma patients compared to healthy individuals, and depletion of T reg cells from the blood of these patients prior to TEM restored T cell migration. The effect of T reg cells was largely dependent on cell-cell contact, but not on IL-10 or TGF-b. In addition, the presence of T reg cells led to reduced T cell attachment to endothelium and decreased production of T cell-recruiting chemokines during TEM. In conclusion, T reg cell-mediated reduction of T cell TEM may reduce T cell recruitment in patients with epithelial malignancies, thereby hampering anti-tumour responses.

Helicobacter pylori infection is associated with pronounced infiltration of granulocytes and lymphocytes into the gastric mucosa, resulting in active chronic gastritis that may develop into duodenal ulcer disease or gastric adenocarcinoma. Infiltrating T cells play a major role in the pathology of these diseases, but the signals involved in recruitment of T cells from blood to H. pylori-infected tissues are not well understood. We therefore examined H. pylori-induced T-cell transendothelial migration (TEM). The Transwell system, employing a monolayer of human umbilical vein endothelial cells, was used as a model to study TEM. H. pylori induced a significant T-cell migration, compared to spontaneous migration. CD4؉ and CD8 ؉ T cells migrated to the same extent in response to H. pylori, whereas there was significantly larger transmigration of memory T cells compared to naive T cells. Both H. pylori culture filtrate and urease induced migration, and the presence of the H. pylori cag pathogenicity island increased TEM. T-cell TEM was mediated by LFA-1-ICAM-1 interactions in accordance with an increased ICAM-1 expression on the endothelial cells after contact with H. pylori. Migrating T cells had increased expression of activation marker CD69 and chemokine receptors CXCR3, CCR4, and CCR9. Furthermore, T cells migrating in response to H. pylori secreted Th1 but not Th2 cytokines upon stimulation. In conclusion, our data indicate that live H. pylori and its secreted products contribute to T-cell recruitment to the gastric mucosa and that the responding T cells have an activated memory Th1 phenotype.

No abstract

No abstract