scholarly journals Role of Transcription Factor T-bet Expression by CD4+ Cells in Gastritis Due to Helicobacter pylori in Mice

2006 ◽  
Vol 74 (8) ◽  
pp. 4673-4684 ◽  
Author(s):  
Kathryn A. Eaton ◽  
Lucy H. Benson ◽  
Jennifer Haeger ◽  
Brian M. Gray
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
Transcription Factor ◽  
Scid Mice ◽  
Delayed Type Hypersensitivity ◽  
Necrosis Factor Alpha ◽  
Ifn Γ ◽  
H Pylori ◽  
Cd4 Cell

ABSTRACT Gastritis due to Helicobacter pylori is induced by a Th1-mediated response that is CD4 cell and gamma interferon (IFN-γ) dependent. T-bet is a transcription factor that directs differentiation of and IFN-γ secretion by CD4+ Th1 T cells. The goal of this study was to use two mouse models to elucidate the role of T-bet in gastritis due to H. pylori. C57BL/6J mice, congenic T-bet knockout (KO) mutants, or congenic SCID (severe, combined immunodeficient) mutants were given live H. pylori by oral inoculation. SCID mice were given CD4+ splenocytes from C57BL/6J or T-bet KO mice by intraperitoneal injection. Twelve or 24 weeks after bacterial inoculation, C57BL/6J mice developed moderate gastritis but T-bet KO mice and SCID mice did not. In contrast, SCID recipients of either C57BL/6J T cells or T-bet KO T cells developed gastritis 4 or 8 weeks after adoptive transfer. In recipients of C57BL/6J CD4+ cells but not recipients of T-bet KO cells, gastritis was associated with a delayed-type hypersensitivity response to H. pylori antigen and elevated gastric and serum IFN-γ, interleukin 6, and tumor necrosis factor alpha. In spite of the absence of IFN-γ expression, indicating failure of Th1 differentiation, CD4+ T cells from T-bet KO mice induce gastritis in H. pylori-infected recipient SCID mice. This indicates that Th1-independent mechanisms can cause gastric inflammation and disease due to H. pylori.

scholarly journals Adoptive Transfer of CD4+ T Cells Specific for Subunit A of Helicobacter pylori Urease ReducesH. pylori Stomach Colonization in Mice in the Absence of Interleukin-4 (IL-4)/IL-13 Receptor Signaling

2001 ◽  
Vol 69 (3) ◽  
pp. 1714-1721 ◽  
Author(s):  
Bernadette Lucas ◽  
Dirk Bumann ◽  
Anna Walduck ◽  
Jan Koesling ◽  
Leyla Develioglu ◽  
...  
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
Adoptive Transfer ◽  
Bacterial Load ◽  
Interleukin 4 ◽  
T Cell Epitopes ◽  
Necrosis Factor Alpha ◽  
Subunit A ◽  
Ifn Γ ◽  
H Pylori

ABSTRACT Protection in the murine model of Helicobacter pyloriinfection may be mediated by CD4+ T cells, but the mechanism remains unclear. To better understand how protection occurs in this model, we generated and characterized H. pyloriurease-specific CD4+ T cells from BALB/c mice immunized with Salmonella enterica serovar Typhimurium expressingH. pylori urease (subunits A and B). The CD4+ T cells were found to be specific for subunit A (UreA). Upon antigen-specific stimulation, expression of interleukin 4 (IL-4), IL-10, gamma interferon (IFN-γ), and tumor necrosis factor alpha was induced. Immunocytochemical analysis showed that the majority of cells produced IFN-γ and IL-10. Adoptive transfer of the UreA-specific CD4+ T cells into naive syngeneic recipients led to a threefold reduction in the number of bacteria in the recipient group when compared to that in the nonrecipient group. Stomach colonization was also reduced significantly after transfer of these cells into patently infected mice. Adoptive transfer of UreA-specific CD4+ T cells into IL-4 receptor α chain-deficient BALB/c mice indicated that IL-4 and IL-13 were not critical in the control of bacterial load. In addition, synthetic peptides were used to identify three functional T-cell epitopes present in subunit A which were recognized by the UreA-specific T cells. Analysis of H. pylori-specific cellular immune responses in recipient challenged and nonrecipient infected mice indicated a strong local restriction of the response in infected animals. The implications of these findings for the mechanism of protection and the development of peptide-based vaccination are discussed.

scholarly journals Complex T Cell Interactions Contribute to Helicobacter pylori Gastritis in Mice

2012 ◽  
Vol 81 (3) ◽  
pp. 740-752 ◽  
Author(s):  
Brian M. Gray ◽  
Clinton A. Fontaine ◽  
Sara A. Poe ◽  
Kathryn A. Eaton
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Published Data ◽  
Proinflammatory Response ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Tnf Α ◽  
Ifn Γ ◽  
H Pylori

ABSTRACTDisease due to the gastric pathogenHelicobacter pylorivaries in severity from asymptomatic to peptic ulcer disease and cancer. Accumulating evidence suggests that one source of this variation is an abnormal host response. The goal of this study was to use a mouse model ofH. pylorigastritis to investigate the roles of regulatory T cells (Treg) as well as proinflammatory T cells (Th1 and Th17) in gastritis, gastric T cell engraftment, and gastric cytokine production. Our results support published data indicating that severe gastritis in T cell recipient mice is due to failure of Treg engraftment, that Treg ameliorate gastritis, and that the proinflammatory response is attributable to interactions between several cell subsets and cytokines. We confirmed that gamma interferon (IFN-γ) is essential for induction of gastritis but showed that IFN-γ-producing CD4 T cells are not necessary. Interleukin 17A (IL-17A) also contributed to gastritis, but to a lesser extent than IFN-γ. Tumor necrosis factor alpha (TNF-α) and IL-17F were also elevated in association with disease. These results indicate that whileH. pylori-specific CD4+T cells and IFN-γ are both essential for induction of gastritis due toH. pylori, IFN-γ production by T cells is not essential. It is likely that other proinflammatory cytokines, such as IL-17F and TNF-α, shown to be elevated in this model, also contribute to the induction of disease. We suggest that gastritis due toH. pyloriis associated with loss of immunoregulation and alteration of several cytokines and cell subsets and cannot be attributed to a single immune pathway.

scholarly journals Helicobacter pylori with a Truncated Lipopolysaccharide O Chain Fails To Induce Gastritis in SCID Mice Injected with Splenocytes from Wild-Type C57BL/6J Mice

2004 ◽  
Vol 72 (7) ◽  
pp. 3925-3931 ◽  
Author(s):  
K. A. Eaton ◽  
S. M. Logan ◽  
P. E. Baker ◽  
R. A. Peterson ◽  
M. A. Monteiro ◽  
...  
Keyword(s):  
Immune Response ◽  
Helicobacter Pylori ◽  
Immune Responses ◽  
Scid Mice ◽  
Delayed Type Hypersensitivity ◽  
Wild Type ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Ifn Γ ◽  
H Pylori

ABSTRACT The goal of this study was to determine whether Helicobacter pylori lipopolysaccharide (LPS) O-chain polysaccharide contributes to gastritis in a mouse model. C57BL/6J or C57BL/6-Prkdcscid (severe combined immunodeficient [SCID]) mice were inoculated with H. pylori strain SS1 or SS1::0826kan, in which a β-1,4-galactosyltransferase (HP0826), an LPS biosynthetic enzyme, had been disrupted. H. pylori strain SS1::0826kan expresses truncated LPS lacking O chain. Recipient SCID mice were given C57BL/6J splenocytes by intraperitoneal injection. Bacterial colonization, gastric lesions (gastritis, neutrophilic infiltration, and gastric epithelial metaplasia), cellular (delayed-type hypersensitivity) and humoral immune responses to H. pylori sonicate, and gastric gamma interferon (IFN-γ) mRNA expression were quantified. Recipient SCID mice colonized by H. pylori strain SS1 developed extensive gastritis with loss of normal fundic gland morphology. In contrast, gastric mucosa of recipient SCID mice colonized by H. pylori strain SS1::0826kan was not statistically distinguishable from that of uninfected recipient mice. Delayed-type hypersensitivity and humoral immune responses were detected in infected mice inoculated with wild-type SS1, but not with SS1::0826kan. IFN-γ transcription was lower in mice infected with SS1::0826kan than in mice infected with SS1. In this model of rapidly progressive gastritis due to H. pylori, the O chain contributed to the extent of gastritis and to the host immune response. These data support a role for H. pylori LPS O chain in direct induction of the host immune response leading to gastritis and gastric damage and are in contrast to protein antigens, such as urease and cag products which do not contribute to gastritis in mice.

scholarly journals Role of Gamma Interferon in Helicobacter pylori Induction of Inflammatory Mediators during Murine Infection

2002 ◽  
Vol 70 (6) ◽  
pp. 3295-3299 ◽  
Author(s):  
Marygorret Obonyo ◽  
Donald G. Guiney ◽  
Julia Harwood ◽  
Joshua Fierer ◽  
Sheri P. Cole
Keyword(s):  
Helicobacter Pylori ◽  
Gene Knockout ◽  
Gamma Interferon ◽  
Epithelial Cell Line ◽  
Inos Mrna ◽  
Inflammatory Protein ◽  
Ifn Γ ◽  
H Pylori ◽  
Oxide Synthase

ABSTRACT Gamma interferon (IFN-γ) has been proposed to play an important role in Helicobacter-related gastritis. Using the IFN-γ gene knockout (IFN-γ−/−) mouse model and a murine gastric epithelial cell line, GSM06, we demonstrated that Helicobacter pylori maximally induced macrophage inflammatory protein-2 (MIP-2) and inducible nitric oxide synthase (iNOS) mRNA only in wild-type mice. MIP-2 and iNOS mRNA were also induced by H. pylori in GSM06 cells. Induction of cyclooxygenase 2 mRNA through IFN-γ was demonstrated in GSM06 cells. These data indicate that IFN-γ mediates the induction of MIP-2 and iNOS mRNA expression by H. pylori in mice.

scholarly journals Protection against Intestinal Amebiasis by a Recombinant Vaccine Is Transferable by T Cells and Mediated by Gamma Interferon

2009 ◽  
Vol 77 (9) ◽  
pp. 3909-3918 ◽  
Author(s):  
Xiaoti Guo ◽  
Lisa Barroso ◽  
Steven M. Becker ◽  
David M. Lyerly ◽  
Thomas S. Vedvick ◽  
...  
Keyword(s):  
T Cells ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Vaccine Protection ◽  
Adjuvant System ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Intestinal Amebiasis

ABSTRACT We have previously shown that vaccination with purified Entamoeba histolytica Gal/GalNAc lectin or recombinant subunits can protect mice from intestinal amebiasis upon intracecal challenge. In this study, we demonstrated with adoptive-transfer experiments that this lectin vaccine protection is mediated by T cells but not serum. The cell-mediated immune (CMI) response was characterized by significant gamma interferon (IFN-γ), interleukin 12 (IL-12), IL-2, IL-10, and IL-17 production. To move toward a human vaccine, we switched to a recombinant protein and tested a range of adjuvants and routes appropriate for humans. We found that subcutaneous delivery of LecA with IDRI's adjuvant system EM014 elicited a potent Th1-type CMI profile and provided significant protection, as measured by culture negativity (79% efficacy); intranasal immunization with cholera toxin provided 56% efficacy; and alum induced a Th2-type response that protected 62 to 68% of mice. Several antibody and CMI cytokine responses were examined for correlates of protection, and prechallenge IFN-γ+ or IFN-γ-, IL-2-, and tumor necrosis factor alpha-triple-positive CD4 cells in blood were statistically associated with protection. To test the role of IFN-γ in LecA-mediated protection, we neutralized IFN-γ in LecA-immunized mice and found that it abrogated the protection conferred by vaccination. These data demonstrate that CMI is sufficient for vaccine protection from intestinal amebiasis and reveal an important role for IFN-γ, even in the setting of alum.

scholarly journals Protective and Pathological Functions of CD8+T Cells in Leishmania braziliensis Infection

2014 ◽  
Vol 83 (3) ◽  
pp. 898-906 ◽  
Author(s):  
Thiago Marconi Cardoso ◽  
Álvaro Machado ◽  
Diego Luiz Costa ◽  
Lucas P. Carvalho ◽  
Adriano Queiroz ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Granzyme B ◽  
Delayed Type Hypersensitivity ◽  
Leishmania Braziliensis ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Factor Alpha ◽  
Ifn Γ

Cutaneous leishmaniasis (CL) caused byLeishmania braziliensisis characterized by a strong Th1 response that leads to skin lesion development. In areas whereL. braziliensistransmission is endemic, up to 15% of healthy subjects have tested positive for delayed-type hypersensitivity to soluble leishmania antigen (SLA) and are considered to have subclinical (SC) infection. SC subjects produce less gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) than do CL patients, but they are able to control the infection. The aim of this study was to characterized the role of CD8+T cells in SC infection and in CL. Peripheral blood mononuclear cells (PBMC) were stimulated with SLA to determine the frequencies of CD4+IFN-γ+and CD8+IFN-γ+T cells. Monocytes from PBMC were infected withL. braziliensisand cocultured with CD8+T cells, and the frequencies of infected monocytes and levels of cytotoxicity markers, target cell apoptosis, and granzyme B were determined. The frequency of CD8+IFN-γ+cells after SLA stimulation was higher for SC individuals than for CL patients. The frequency of infected monocytes in SC cells was lower than that in CL cells. CL CD8+T cells induced more apoptosis of infected monocytes than did SC CD8+T cells. Granzyme B production in CD8+T cells was higher in CL than in SC cells. While the use of a granzyme B inhibitor decreased the number of apoptotic cells in the CL group, the use of z-VAD-FMK had no effect on the frequency of these cells. These results suggest that CL CD8+T cells are more cytotoxic and may be involved in pathology.

scholarly journals Role of T Cells and Gamma Interferon during Induction of Hypersensitivity to Lipopolysaccharide by Toxic Shock Syndrome Toxin 1 in Mice

2001 ◽  
Vol 69 (3) ◽  
pp. 1256-1264 ◽  
Author(s):  
Martin M. Dinges ◽  
Patrick M. Schlievert
Keyword(s):  
T Cells ◽  
Toxic Shock Syndrome ◽  
Gamma Interferon ◽  
Scid Mice ◽  
Enhancement Effect ◽  
Toxic Shock ◽  
Tnf Α ◽  
Ifn Γ ◽  
Toxic Shock Syndrome Toxin

ABSTRACT The superantigenic function of toxic shock syndrome toxin 1 (TSST-1) is generally regarded as an important determinant of its lethal effects in humans or experimental animals. This study examined the role of superantigenicity in a BALB/c mouse model of lethal TSST-1-induced hypersensitivity to lipopolysaccharide (LPS). In this model, TSST-1 greatly potentiated both LPS-induced lethality, as well as LPS-induced serum tumor necrosis factor alpha (TNF-α) activity. Although BALB/c-SCID mice were resistant to these LPS enhancement effects of TSST-1, BALB/c-SCID mice reconstituted with T cells were completely susceptible to the enhancement effect of TSST-1 on LPS-induced serum TNF-α. Mice pretreated with cyclosporine (Cs) or neutralizing antibodies against gamma interferon (IFN-γ) did not develop lethal LPS hypersensitivity when injected with TSST-1, and these agents reduced the enhancement effect of TSST-1 on LPS-induced serum TNF-α by 99 and 85%, respectively. Cs pretreatment also completely inhibited the known capacity of TSST-1 to amplify LPS-induced levels of IFN-γ in serum. In contrast, mice given Cs after a priming injection of TSST-1, but before LPS, still exhibited lethal hypersensitivity to LPS. Cs given after TSST-1 also did not inhibit enhancement of LPS-induced serum TNF-α by TSST-1 but inhibited the enhancement effect of TSST-1 on LPS-induced serum IFN-γ by 50%. These experiments support the theory that TSST-1-induced hypersensitivity to LPS is mediated primarily by IFN-γ derived from superantigen-activated T cells.

scholarly journals Transfer of Antigen-Pulsed Dendritic Cells Induces Specific T-Cell Proliferation and a Therapeutic Effect against Long-Term Helicobacter pylori Infection in Mice

2006 ◽  
Vol 74 (2) ◽  
pp. 984-993 ◽  
Author(s):  
Satoshi Otsu ◽  
Kazuyo Gotoh ◽  
Tetsu Yamashiro ◽  
Junpei Yamagata ◽  
Kouichirou Shin ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Interleukin 10 ◽  
Cell Mediated Immunity ◽  
Mouse Bone Marrow ◽  
Peptic Ulcers ◽  
Th1 Cell ◽  
Necrosis Factor Alpha ◽  
Ifn Γ ◽  
H Pylori

ABSTRACT Helicobacter pylori causes persistent infection of the stomach and results in chronic gastritis and peptic ulcers. Jaws II cells, derived from mouse bone marrow, were pulsed with live or formalin-killed or whole-cell sonicates (WCS) of H. pylori. Representative cell surface molecules were expressed at substantial levels on Jaws II cells, indicating that appropriate maturation of the cells was achieved with the three H. pylori antigens without any significant differences. H. pylori WCS-pulsed Jaws II cells secreted a significant amount of tumor necrosis factor alpha into the culture supernatant. The naïve T cells exposed to the WCS-pulsed Jaws II cells showed significant proliferation and gamma interferon (IFN-γ) and interleukin-10 (IL-10) production in vitro. A 2-log reduction in the number of colonizing bacteria was observed in the mice treated with the WCS-pulsed Jaws II cells; however, no significant reductions were achieved in mice treated with Jaws II cells pulsed with other H. pylori antigens. Up-regulated production of IFN-γ and IL-10 was observed in the stomachs of the mice treated with the WCS-pulsed Jaws II cells, which is consistent with the result obtained in vitro. There were no differences in gastritis scores or H. pylori-specific antibody titers among the mice treated with Jaws II cells pulsed with the three different H. pylori antigens. The results suggest that Th1 cell-mediated immunity in combination with Th2 cell-mediated immunity plays a role in reducing colonizing bacterial numbers in mice with chronic H. pylori infections.

scholarly journals Role of Local Cytokines in Increased Gastric Expression of the Secretory Component in Helicobacter pylori Infection

1999 ◽  
Vol 67 (9) ◽  
pp. 4921-4925 ◽  
Author(s):  
Ingela Ahlstedt ◽  
Catharina Lindholm ◽  
Hans Lönroth ◽  
Annika Hamlet ◽  
Ann-Mari Svennerholm ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Secretory Component ◽  
Interleukin 4 ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
H Pylori ◽  
Lamina Propria Lymphocytes ◽  
Necrosis Factor

ABSTRACT Using immunohistochemical staining, we examined the presence of secretory component (SC) on epithelial cells in gastric and duodenal biopsy specimens collected from Helicobacter pylori-infected individuals and healthy controls. Gastric epithelial cells from healthy volunteers expressed low, but detectable, levels of SC. In contrast, significantly higher level of expression of SC (P < 0.001) was observed on epithelial cells in the antra of H. pylori-infected individuals. The antral SC expression correlated with staining for gamma interferon of intraepithelial and lamina propria lymphocytes (r s = 0.76 and 0.69, respectively,P < 0.001) and correlated weakly with production of tumor necrosis factor alpha (r s = 0.43,P < 0.05), but it did not correlate at all with interleukin-4 production.

scholarly journals Human Dendritic Cells following Aspergillus fumigatus Infection Express the CCR7 Receptor and a Differential Pattern of Interleukin-12 (IL-12), IL-23, and IL-27 Cytokines, Which Lead to a Th1 Response

2006 ◽  
Vol 74 (3) ◽  
pp. 1480-1489 ◽  
Author(s):  
Valérie Gafa ◽  
Roberto Lande ◽  
Maria Cristina Gagliardi ◽  
Martina Severa ◽  
Elena Giacomini ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Aspergillus Fumigatus ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Th1 Response ◽  
Ifn Γ ◽  
Human Dendritic Cells ◽  
The Impact

ABSTRACT Aspergillus fumigatus is the most prevalent airborne fungal pathogen and causes fatal invasive aspergillosis in immunocompromised patients. Given the essential role of dendritic cells (DC) in initiating and regulating immune responses, we investigated the impact of A. fumigatus conidial infection on human DC. A. fumigatus conidia were rapidly internalized and induced the release of tumor necrosis factor alpha within the first 8 h. After A. fumigatus infection, the majority of DC underwent full maturation, although CCR7 expression was observed only in DC that had internalized the conidia. Additionally, the analysis of regulatory cytokines showed that infected DC simultaneously produced interleukin-12p70 (IL-12p70) and significant amounts of IL-10. IL-10 neutralization was not able to further increase IL-12p70 production from infected DC. Whereas the central role of IL-12 in the generation of Th1 cells has long been appreciated, recently two other members of the IL-12 family, IL-23 and IL-27, were reported to play important roles in the regulation of gamma interferon (IFN-γ) production from naïve and memory T cells. A. fumigatus-infected DC were also able to express high levels of IL-23p19 and low levels of IL-27p28 at later stages of infection. According to this expression pattern, A. fumigatus-infected DC were able to prime IFN-γ production of naïve T cells. Thus, this study on the expression of the new IL-12 family members controlling the Th1 response sheds light on a novel aspect of the contribution of DC to anti-Aspergillus immunity.

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