Mucosal FOXP3 -Expressing CD4 ⁺ CD25 ^high Regulatory T Cells in Helicobacter pylori -Infected Patients

Abstract

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...

Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer

“…With regards to gastric mucosa, there are several reports describing the presence of Helicobacter pylori infection-associated Foxp3 þ T regs (Lundgren et al, 2005;Enarsson et al, 2006). Since, in the present cohort with gastric cancer, there was no information on H. pylori infection, it is impossible to evaluate the influence of this infection.…”

Clinical implications and characteristics of factor forkhead box protein 3 in gastric cancer

“…Although the factors and molecular events associated with the progression of gastric cancer are complex and are not well established, FOXP3 has been shown to play an important role in Tregs in gastric cancer invasion (18). In this study, we assessed the expression and subcellular localization of FOXP3 in gastric cancer cell lines and tissues.…”

CD4+ regulatory T cells in gastric cancer mucosa are proliferating and express high levels of IL-10 but little TGF-β

“…CD25 high Treg in the mucosa [20,21] and that the frequency of FOXP3-expressing T cells is increased in the gastric tumor mucosa compared to tumor-free gastric mucosa [22]. The increase in FOXP3-expressing Tregs in tumor mucosa may be caused by increased recruitment of CCR4-expressing Tregs into the tumor [22,23].…”