scholarly journals Role of Gastric Epithelial Cell-Derived Transforming Growth Factor β in Reduced CD4+T Cell Proliferation and Development of Regulatory T Cells during Helicobacter pylori Infection

2011 ◽  
Vol 79 (7) ◽  
pp. 2737-2745 ◽  
Author(s):  
Ellen J. Beswick ◽  
Iryna V. Pinchuk ◽  
Rachel B. Earley ◽  
David A. Schmitt ◽  
Victor E. Reyes
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
T Cell Responses ◽  
Transforming Growth Factor Β ◽  
Content Type ◽  
Cell Responses ◽  
H Pylori

ABSTRACTGastric epithelial cells (GECs) express the class II major histocompatibility complex (MHC) and costimulatory molecules, enabling them to act as antigen-presenting cells (APCs) and affect local T cell responses. DuringHelicobacter pyloriinfection, GECs respond by releasing proinflammatory cytokines and by increasing the surface expression of immunologically relevant receptors, including class II MHC. The CD4+T cell response duringH. pyloriinfection is skewed toward a Th1 response, but these cells remain hyporesponsive. Activated T cells show decreased proliferation duringH. pyloriinfection, and CD4+CD25+FoxP3+regulatory T cells (Tregs) are present at the site of infection. In this study, we examined the mechanisms surrounding the CD4+T cell responses duringH. pyloriinfection and found that transforming growth factor β (TGF-β) plays a major role in these responses. GECs produced TGF-β1 and TGF-β2 in response to infection. Activated CD4+T cells in culture withH. pylori-treated GECs were decreased in proliferation but increased upon neutralization of TGF-β. Naïve CD4+T cell development into Tregs was also enhanced in the presence of GEC-derived TGF-β. Herein, we demonstrate a role for GEC-produced TGF-β in the inhibition of CD4+T cell responses seen duringH. pyloriinfection.

scholarly journals Regulation of Human CD4+ αβ T-Cell-Receptor-Positive (TCR+) and γδ TCR+ T-Cell Responses to Mycobacterium tuberculosis by Interleukin-10 and Transforming Growth Factor β

1999 ◽  
Vol 67 (12) ◽  
pp. 6461-6472 ◽  
Author(s):  
Roxana E. Rojas ◽  
Kithiganahalli N. Balaji ◽  
Ahila Subramanian ◽  
W. Henry Boom
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Transforming Growth Factor Β ◽  
T Cell Subsets ◽  
Cell Responses

ABSTRACT Mycobacterium tuberculosis is the etiologic agent of human tuberculosis and is estimated to infect one-third of the world's population. Control of M. tuberculosis requires T cells and macrophages. T-cell function is modulated by the cytokine environment, which in mycobacterial infection is a balance of proinflammatory (interleukin-1 [IL-1], IL-6, IL-8, IL-12, and tumor necrosis factor alpha) and inhibitory (IL-10 and transforming growth factor β [TGF-β]) cytokines. IL-10 and TGF-β are produced by M. tuberculosis-infected macrophages. The effect of IL-10 and TGF-β on M. tuberculosis-reactive human CD4+and γδ T cells, the two major human T-cell subsets activated byM. tuberculosis, was investigated. Both IL-10 and TGF-β inhibited proliferation and gamma interferon production by CD4+ and γδ T cells. IL-10 was a more potent inhibitor than TGF-β for both T-cell subsets. Combinations of IL-10 and TGF-β did not result in additive or synergistic inhibition. IL-10 inhibited γδ and CD4+ T cells directly and inhibited monocyte antigen-presenting cell (APC) function for CD4+ T cells and, to a lesser extent, for γδ T cells. TGF-β inhibited both CD4+ and γδ T cells directly and had little effect on APC function for γδ and CD4+ T cells. IL-10 down-regulated major histocompatibility complex (MHC) class I, MHC class II, CD40, B7-1, and B7-2 expression on M. tuberculosis-infected monocytes to a greater extent than TGF-β. Neither cytokine affected the uptake of M. tuberculosis by monocytes. Thus, IL-10 and TGF-β both inhibited CD4+ and γδ T cells but differed in the mechanism used to inhibit T-cell responses to M. tuberculosis.

scholarly journals Helicobacter pylori Infection in a Pig Model Is Dominated by Th1 and Cytotoxic CD8+T Cell Responses

2013 ◽  
Vol 81 (10) ◽  
pp. 3803-3813 ◽  
Author(s):  
Barbara Kronsteiner ◽  
Josep Bassaganya-Riera ◽  
Casandra Philipson ◽  
Monica Viladomiu ◽  
Adria Carbo ◽  
...  
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
T Cell ◽  
T Cell Responses ◽  
Pig Model ◽  
Content Type ◽  
Functional Changes ◽  
Gastric Pathology ◽  
Cell Responses ◽  
H Pylori

ABSTRACTHelicobacter pyloriinfection is the leading cause for peptic ulcer disease and gastric adenocarcinoma. Mucosal T cell responses play an important role in mediatingH. pylori-related gastric immunopathology. While induced regulatory T (iTreg) cells are required for chronic colonization without disease, T helper 1 (Th1) effector responses are associated with lower bacterial loads at the expense of gastric pathology. Pigs were inoculated with eitherH. pyloristrain SS1 or J99. Phenotypic and functional changes in peripheral blood mononuclear cell (PBMC) populations were monitored weekly, and mucosal immune responses and bacterial loads were assessed up to 2 months postinfection. BothH. pyloristrains elicited a Th1 response characterized by increased percentages of CD4+Tbet+cells and elevated gamma interferon (IFN-γ) mRNA in PBMCs. A subset of CD8+T cells expressing Tbet and CD16 increased following infection. Moreover, a significant increase in perforin and granzyme mRNA expression was observed in PBMCs of infected pigs, indicating a predominant cytotoxic immune response. Infiltration of B cells, myeloid cells, T cells expressing Treg- and Th17-associated transcription factors, and cytotoxic T cells was found in the gastric lamina propria of both infected groups. Interestingly, based on bacterial reisolation data, strain SS1 showed greater capacity to colonize and/or persist in the gastric mucosa than did strain J99. This novel pig model of infection closely mimics human gastric pathology and presents a suitable avenue for studying effector and regulatory responses towardH. pyloridescribed in humans.

scholarly journals Helicobacter pylori VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Aleksandra Altobelli ◽  
Michael Bauer ◽  
Karelia Velez ◽  
Timothy L. Cover ◽  
Anne Müller
Keyword(s):  
Helicobacter Pylori ◽  
T Cell ◽  
Persistent Infection ◽  
Myeloid Cells ◽  
T Cell Responses ◽  
T Cell Differentiation ◽  
Content Type ◽  
Effector T Cell ◽  
Cell Responses ◽  
H Pylori

ABSTRACT The gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter-host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the Helicobacter immunomodulator VacA to H. pylori-specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3+) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type H. pylori but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-β expression in macrophages. Taken together, the results are consistent with the idea that H. pylori creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors H. pylori persistence, and affects immunity at distant sites. IMPORTANCE Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.

scholarly journals Transforming growth factor-β negatively modulates T-cell responses in sepsis

FEBS Letters ◽  
1997 ◽  
Vol 402 (2-3) ◽  
pp. 213-218 ◽  
Author(s):  
Sarfraz Ahmad ◽  
Mashkoor A Choudhry ◽  
Ravi Shankar ◽  
Mohammed M Sayeed
Keyword(s):  
T Cell ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
T Cell Responses ◽  
Transforming Growth Factor Β ◽  
Cell Responses

scholarly journals Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease

2017 ◽  
Vol 85 (8) ◽  
Author(s):  
Lucia Trotta ◽  
Kathleen Weigt ◽  
Katina Schinnerling ◽  
Anika Geelhaar-Karsch ◽  
Gerrit Oelkers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
T Cell Responses ◽  
Tropheryma Whipplei ◽  
Content Type ◽  
Cell Responses ◽  
Ifn Γ

ABSTRACT Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward Tropheryma whipplei in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from T. whipplei was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-γ) were determined in T cells by flow cytometry. Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of T. whipplei, the proportions of activated effector CD4+ T cells, determined as CD40L+ IFN-γ+, were significantly lower in patients with CWD than in healthy controls; CD8+ T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and T. whipplei-specific degranulation, although CD69+ IFN-γ+ CD8+ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei-derived proteins. Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against T. whipplei to control bacterial spreading. The lack of specific T-cell responses against these T. whipplei-derived proteins may contribute to the pathogenesis of CWD.

scholarly journals Long-Term Immunity to Trypanosoma cruzi in the Absence of Immunodominanttrans-Sialidase-Specific CD8+T Cells

2016 ◽  
Vol 84 (9) ◽  
pp. 2627-2638 ◽  
Author(s):  
Charles S. Rosenberg ◽  
Weibo Zhang ◽  
Juan M. Bustamante ◽  
Rick L. Tarleton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Trypanosoma Cruzi ◽  
T Cell Responses ◽  
Content Type ◽  
Cell Responses ◽  
Pathogen Control ◽  
Immunodominant Epitopes

Trypanosoma cruziinfection drives the expansion of remarkably focused CD8+T cell responses targeting epitopes encoded by varianttrans-sialidase (TS) genes. Infection of C57BL/6 mice withT. cruziresults in up to 40% of all CD8+T cells committed to recognition of the dominant TSKB20 and subdominant TSKB18 TS epitopes. However, despite this enormous response, these mice fail to clearT. cruziinfection and subsequently develop chronic disease. One possible reason for the failure to cureT. cruziinfection is that immunodomination by these TS-specific T cells may interfere with alternative CD8+T cell responses more capable of complete parasite elimination. To address this possibility, we created transgenic mice that are centrally tolerant to these immunodominant epitopes. Mice expressing TSKB20, TSKB18, or both epitopes controlledT. cruziinfection and developed effector CD8+T cells that maintained an activated phenotype. Memory CD8+T cells from drug-cured TSKB-transgenic mice rapidly responded to secondaryT. cruziinfection. In the absence of the response to TSKB20 and TSKB18, immunodominance did not shift to other known subdominant epitopes despite the capacity of these mice to expand epitope-specific T cells specific for the model antigen ovalbumin expressed by engineered parasites. Thus, CD8+T cell responses tightly and robustly focused on a few epitopes within variant TS antigens appear to neither contribute to, nor detract from, the ability to controlT. cruziinfection. These data also indicate that the relative position of an epitope within a CD8+immunodominance hierarchy does not predict its importance in pathogen control.

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

2003 ◽  
Vol 71 (4) ◽  
pp. 1755-1762 ◽  
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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