Mucosal FOXP3-Expressing CD4+ CD25high 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+ CD25high 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 FOXP3, a key gene for the development and function of regulatory T cells, as well as high levels of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) protein. In contrast, mucosal CD4+ CD25low and CD4+ CD25− cells express little FOXP3 mRNA and low levels of the CTLA-4 protein. Mucosal CD4+ CD25high T cells are present in individuals with asymptomatic H. pylori infections as well as in duodenal ulcer patients. The frequencies of CD4+ CD25high cells are also increased in the stomachs of H. pylori-infected patients with gastric adenocarcinoma, particularly in cancer-affected tissues. These findings suggest that regulatory T cells may suppress mucosal immune responses and thereby contribute to the persistence of H. pylori infections.

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Helicobacterpylori-Specific CD4+ CD25high Regulatory T Cells Suppress Memory T-Cell Responses to H. pylori in Infected Individuals

Infection and Immunity ◽

10.1128/iai.71.4.1755-1762.2003 ◽

2003 ◽

Vol 71 (4) ◽

pp. 1755-1762 ◽

Cited By ~ 215

Author(s):

Anna Lundgren ◽

Elisabeth Suri-Payer ◽

Karin Enarsson ◽

Ann-Mari Svennerholm ◽

B. Samuel Lundin

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Interleukin 2 ◽

T Cell Responses ◽

Duodenal Mucosa ◽

Peptic Ulcers ◽

Memory Cells ◽

Cell Responses ◽

H Pylori

ABSTRACT 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+ CD25high T cells during infection. The stimulation of CD4+ peripheral blood T cells with monocyte-derived dendritic cells pulsed with a membrane preparation of H. pylori resulted in proliferation and gamma interferon production in both infected and uninfected individuals. Sorted memory cells from infected individuals responded less than cells from uninfected subjects, and the unresponsiveness could be abolished by depletion of CD4+ CD25high regulatory T cells or the addition of interleukin 2. Furthermore, CD4+ CD25high T cells suppressed H. pylori-induced responses in cocultures with CD25low/− cells. Tetanus toxoid induced comparable responses in memory cells from infected and uninfected individuals in both the presence and the absence of regulatory T cells, suggesting that the suppression was H. pylori specific. In conclusion, we have shown that H. pylori-infected individuals have impaired memory CD4+ T-cell responses to H. pylori that are linked to the presence of H. pylori-specific regulatory T cells that actively suppress the responses.

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CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

Journal of Experimental Medicine ◽

10.1084/jem.20081811 ◽

2009 ◽

Vol 206 (2) ◽

pp. 421-434 ◽

Cited By ~ 160

Author(s):

Randall H. Friedline ◽

David S. Brown ◽

Hai Nguyen ◽

Hardy Kornfeld ◽

JinHee Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cell Function ◽

Cytotoxic T Lymphocyte ◽

Critical Role ◽

Lymphoproliferative Disease ◽

In Trans ◽

And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

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Function and recruitment of mucosal regulatory T cells in human chronic Helicobacter pylori infection and gastric adenocarcinoma

Clinical Immunology ◽

10.1016/j.clim.2006.07.002 ◽

2006 ◽

Vol 121 (3) ◽

pp. 358-368 ◽

Cited By ~ 67

Author(s):

Karin Enarsson ◽

Anna Lundgren ◽

Bert Kindlund ◽

Mikael Hermansson ◽

Giovanna Roncador ◽

...

Keyword(s):

T Cells ◽

Helicobacter Pylori ◽

Regulatory T Cells ◽

Gastric Adenocarcinoma ◽

Helicobacter Pylori Infection

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Wild-Type and Interleukin-10-Deficient Regulatory T Cells Reduce Effector T-Cell-Mediated Gastroduodenitis in Rag2−/− Mice, but Only Wild-Type Regulatory T Cells Suppress Helicobacter pylori Gastritis

Infection and Immunity ◽

10.1128/iai.01788-06 ◽

2007 ◽

Vol 75 (6) ◽

pp. 2699-2707 ◽

Cited By ~ 34

Author(s):

Chung-Wei Lee ◽

Varada P. Rao ◽

Arlin B. Rogers ◽

Zhongming Ge ◽

Susan E. Erdman ◽

...

Keyword(s):

T Cells ◽

Helicobacter Pylori ◽

Regulatory T Cells ◽

Inflammatory Cytokine ◽

Interleukin 10 ◽

Cytokine Expression ◽

Cell Transfer ◽

Wild Type ◽

H Pylori ◽

Corpus Gastritis

ABSTRACT CD4+ CD45RBhi CD25− effector T cells (TE) promote Helicobacter pylori gastritis in mice, and CD4+ CD45RBlo CD25+ regulatory T cells (TR) are anti-inflammatory. Using adoptive transfer into H. pylori-infected Rag2−/− mice, we evaluated effects of wild-type (wt) C57BL/6 or congenic interleukin-10-deficient (IL-10−/−) TR cells on gastritis, gastric cytokines, and H. pylori colonization. Infected Rag2−/− mice colonized in the corpus and antrum with 105 to 106 H. pylori CFU/gram without associated gastritis. TE cell transfer caused morbidity and an H. pylori-independent pangastritis and duodenitis (gastroduodenitis) associated with increased expression of gamma interferon (IFN-γ) and tumor necrosis factor alpha. TE cell transfer to H. pylori-infected mice led to additive corpus gastritis associated with inflammatory cytokine expression and reduced colonization. wt TR cells reduced morbidity, H. pylori corpus gastritis, gastroduodenitis, and inflammatory cytokine expression and reversed the decline in H. pylori colonization attributable to TE cells. Although less effective than wt TR cells, IL-10−/− TR cells also reduced morbidity and gastroduodenitis but did not reduce H. pylori corpus gastritis or impact TE cell inhibition of colonization. Gastric tissues from mice receiving wt TR cells expressed higher levels of Foxp3 compared to recipients of IL-10−/− TR cells, consistent with lower regulatory activity of IL-10−/− TR cells. These results demonstrate that wt TR cells suppressed TE-cell-mediated H. pylori-independent gastroduodenitis and H. pylori-dependent corpus gastritis more effectively than IL-10−/− TR cells. Compartmental differences in TE-cell- and H. pylori-mediated inflammation and in regulatory effects between wt TR and IL-10−/− TR cells suggest that IL-10 expression by wt TR cells is important to regulatory suppression of gastric inflammation.

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Upregulation of CCL20 and Recruitment of CCR6+ Gastric Infiltrating Lymphocytes in Helicobacter pylori Gastritis

Infection and Immunity ◽

10.1128/iai.01660-06 ◽

2007 ◽

Vol 75 (9) ◽

pp. 4357-4363 ◽

Cited By ~ 39

Author(s):

Yi-Ying Wu ◽

Hwei-Fang Tsai ◽

We-Cheng Lin ◽

Ping-I Hsu ◽

Chia-Tung Shun ◽

...

Keyword(s):

T Cells ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Inflammatory Response ◽

Chemokine Receptor ◽

Ex Vivo ◽

Peptic Ulcers ◽

Lymphocyte Trafficking ◽

Necrosis Factor Alpha ◽

H Pylori

ABSTRACT Helicobacter pylori infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, and gastric cancer. There is increased T-cell infiltration at the site of infection with H. pylori. CCR6, a specific β-chemokine receptor for CCL20 (MIP-3α/LARC/exodus), has recently been reported to mediate lymphocyte homeostasis and immune responses in mucosal tissue, and it may play a role in chemokine-mediated lymphocyte trafficking during gastric inflammation. In this study, we investigated the role of CCR6 and its ligand, CCL20, in inducing an inflammatory response in the gastric mucosa during H. pylori infection. Gastric infiltrating T lymphocytes were isolated from endoscopic biopsy specimens of H. pylori gastritis patients and analyzed for the expression of the CCR6 chemokine receptor. Our results demonstrated that there was significantly increased CCR6 expression in CD3+ T cells infiltrating the gastric mucosa, and the CCR6 ligand, the CCL20 chemokine, was selectively expressed in inflamed gastric tissues. The production of CCL20 was upregulated in response to H. pylori in gastric epithelial cells when there was stimulation by the proinflammatory cytokines interleukin-1β and tumor necrosis factor alpha. Furthermore, recombinant CCL20 induced lymphocyte chemotaxis migration in fresh gastric T cells ex vivo, indicating that the gastric T cells could migrate toward inflammatory sites via CCR6/CCL20 interaction. Our results suggest that the interaction between CCL20 and CCR6 may play a role in chemokine-mediated lymphocyte trafficking during gastric inflammation in Helicobacter infection.

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Dominant Nonresponsiveness to Helicobacter pylori Infection Is Associated with Production of Interleukin 10 but Not Gamma Interferon

Infection and Immunity ◽

10.1128/iai.68.8.4802-4804.2000 ◽

2000 ◽

Vol 68 (8) ◽

pp. 4802-4804 ◽

Cited By ~ 53

Author(s):

Philip Sutton ◽

Tassia Kolesnikow ◽

Stephen Danon ◽

John Wilson ◽

Adrian Lee

Keyword(s):

Helicobacter Pylori ◽

Gastric Adenocarcinoma ◽

Interleukin 10 ◽

Gamma Interferon ◽

Helicobacter Pylori Infection ◽

Peptic Ulcers ◽

Precursor Lesion ◽

H Pylori

ABSTRACT Helicobacter pylori-induced gastritis is an essential precursor lesion for the development of peptic ulcers or gastric adenocarcinoma. We demonstrate that nonresponsiveness to H. pylori SS1 infection is dominantly inherited in mice. F1 hybrid crosses between a nonresponder mouse and three responder strains all possessed the nonresponder phenotype. Secretion of interleukin-10 but not gamma interferon was associated with nonresponsiveness to infection.

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Helicobacter pylori-Specific CD4+ T Cells Home to and Accumulate in the Human Helicobacter pylori-Infected Gastric Mucosa

Infection and Immunity ◽

10.1128/iai.73.9.5612-5619.2005 ◽

2005 ◽

Vol 73 (9) ◽

pp. 5612-5619 ◽

Cited By ~ 60

Author(s):

Anna Lundgren ◽

Christina Trollmo ◽

Anders Edebo ◽

Ann-Mari Svennerholm ◽

B. Samuel Lundin

Keyword(s):

T Cells ◽

Helicobacter Pylori ◽

Chemokine Receptors ◽

Interleukin 2 ◽

Duodenal Mucosa ◽

Cross Reactivity ◽

Receptor Expression ◽

In Vitro Proliferation ◽

H Pylori

ABSTRACT Helicobacter pylori infects the stomach and duodenal mucosa. T cells are important components of the H. pylori-induced immune response, but little is currently known about how these cells are recruited to the infected mucosa. Here, we have characterized stomach and duodenal T cells isolated from H. pylori-infected and noninfected subjects with regard to subtype, expression of homing and chemokine receptors, and in vitro reactivity to H. pylori antigens. Higher numbers of CD4+ but similar numbers of CD8+ lamina propria T cells were isolated from stomach biopsies from H. pylori-positive compared to H. pylori-negative individuals. CD4+ T cells from infected stomach expressed increased levels of the homing receptor L-selectin and the chemokine receptor CCR4 compared to CD4+ T cells from uninfected stomach. Infected stomach mucosa also contained increased levels of the CCR4 chemokine ligand MDC/CCL22. In contrast, comparable numbers of CD4+ T cells with similar receptor expression were isolated from the duodenum of H. pylori-positive and H. pylori-negative individuals. In vitro proliferation of mucosal T cells was strongly enhanced by the addition of interleukin-2 (IL-2) and IL-7 to the cell cultures. Using this approach, H. pylori-specific T-cell responses were detected in stomach CD4+ T cells from H. pylori-positive but not H. pylori-negative individuals. Duodenal T cells from only a few individuals responded to H. pylori stimulation, and the responsiveness was not restricted to H. pylori-positive individuals, suggesting limited H. pylori specificity in the duodenum and possible cross-reactivity with antigens from other bacteria in this compartment. In conclusion, these results suggest that H. pylori-specific CD4+ T cells preferentially home to and accumulate in the infected stomach and that L-selectin and CCR4/MDC are important for this recruitment.

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