Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21

2005 ◽  
Vol 6 (7) ◽  
pp. 680-688 ◽  
Author(s):  
Lisa M Minter ◽  
Danielle M Turley ◽  
Pritam Das ◽  
Hyun Mu Shin ◽  
Ila Joshi ◽  
...  
Keyword(s):  
T Helper ◽  
Helper Type

scholarly journals The injection of deaggregated gamma globulins in adult mice induces antigen-specific unresponsiveness of T helper type 1 but not type 2 lymphocytes.

1992 ◽  
Vol 175 (1) ◽  
pp. 9-14 ◽  
Author(s):  
D De Wit ◽  
M Van Mechelen ◽  
M Ryelandt ◽  
A C Figueiredo ◽  
D Abramowicz ◽  
...  
Keyword(s):  
T Cells ◽  
Tolerance Induction ◽  
T Helper ◽  
Ifn Gamma ◽  
Specific Antibody Response ◽  
Adult Mice ◽  
Helper Type

Injection of adult mice with high doses of monomeric human gamma globulins (dHGG) has been previously shown to produce a state of peripheral tolerance in both B and T cells. To gain insight into the mechanism of induction and maintenance of adult tolerance in this model, we have analyzed the pattern of lymphokines produced by control and tolerant animals in response to the tolerogen. The data presented indicate that HGG-specific, interleukin 2 (IL-2)- and interferon gamma (IFN-gamma)-producing T cells (thus referred to as T helper type 1 [Th1] cells) are rendered unresponsive after in vivo administration of soluble HGG. In contrast, antigenic stimulation of T cells isolated from tolerant adult mice leads to increased production of IL-4 in vitro. In vivo challenge of dHGG-treated adult animals with hapten-coupled HGG (p-azophenylarsonate [ARS]-HGG) induced a significant ARS-specific antibody response, suggesting that tolerance induction in this model does not completely abrogate tolerogen-specific Th activity in vivo. In agreement with the in vitro data, hapten-specific antibody response of tolerant animals is characterized by a selective deficiency in the IFN-gamma-dependent IgG2a subclass. Injection of immunogenic forms of HGG into tolerant animals also produced an IL-4-dependent increase in total serum IgE levels, indicative of an increased activity of HGG-specific Th2 cells in these animals. The finding that tolerance induction differentially affects Th subpopulations suggests that crossregulation among lymphocyte subsets may play a role in the induction and/or maintenance of acquired tolerance in adults.

scholarly journals Endogenous Interleukin 4 Is Required for Development of Protective CD4+ T Helper Type 1 Cell Responses to Candida albicans

1998 ◽  
Vol 187 (3) ◽  
pp. 307-317 ◽  
Author(s):  
Antonella Mencacci ◽  
Giuseppe Del Sero ◽  
Elio Cenci ◽  
Cristiana Fè d'Ostiani ◽  
Angela Bacci ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Early Stage ◽  
Interleukin 4 ◽  
T Helper ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Helper Type

Interleukin (IL)-4–deficient mice were used to assess susceptibility to systemic or gastrointestinal Candida albicans infections, as well as parameters of innate and elicited T helper immunity. In the early stage of systemic infection with virulent C. albicans, an unopposed interferon (IFN)-γ response renders IL-4–deficient mice more resistant than wild-type mice to infection. Yet, IL-4–deficient mice failed to efficiently control infection in the late stage and succumbed to it. Defective IFN-γ and IL-12 production, but not IL-12 responsiveness, was observed in IL-4–deficient mice that failed to mount protective T helper type 1 cell (Th1)-mediated acquired immunity in response to a live vaccine strain of the yeast or upon mucosal immunization in vivo. In vitro, IL-4 primed neutrophils for cytokine release, including IL-12. However, late treatment with exogenous IL-4, while improving the outcome of infection, potentiated CD4+ Th1 responses even in the absence of neutrophils. These findings indicate that endogenous IL-4 is required for the induction of CD4+ Th1 protective antifungal responses, possibly through the combined activity on cells of the innate and adaptive immune systems.

scholarly journals Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection.

1994 ◽  
Vol 180 (4) ◽  
pp. 1273-1282 ◽  
Author(s):  
M B Graham ◽  
V L Braciale ◽  
T J Braciale
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Primary Role ◽  
T Helper ◽  
Helper Type

T lymphocytes play a primary role in recovery from viral infections and in antiviral immunity. Although viral-specific CD8+ and CD4+ T cells have been shown to be able to lyse virally infected targets in vitro and promote recovery from lethal infection in vivo, the role of CD4+ T lymphocytes and their mechanism(s) of action in viral immunity are not well understood. The ability to further dissect the role that CD4+ T cells play in the immune response to a number of pathogens has been greatly enhanced by evidence for more extensive heterogeneity among the CD4+ T lymphocytes. To further examine the role of CD4+ T cells in the immune response to influenza infection, we have generated influenza virus-specific CD4+ T cell clones from influenza-primed BALB/c mice with differential cytokine secretion profiles that are defined as T helper type 1 (Th1) clones by the production of interleukin 2 (IL-2) and interferon gamma (IFN-gamma), or as Th2 clones by the production of IL-4, IL-5, and IL-10. Our studies have revealed that Th1 clones are cytolytic in vitro and protective against lethal challenge with virus in vivo, whereas Th2 clones are noncytolytic and not protective. Upon further evaluation of these clonal populations we have shown that not only are the Th2 clones nonprotective, but that pulmonary pathology is exacerbated as compared with control mice as evidenced by delayed viral clearance and massive pulmonary eosinophilia. These data suggest that virus-specific CD4+ T cells of the Th2 subset may not play a primary role in virus clearance and recovery and may lead to immune mediated potentiation of injury.

scholarly journals Selective Expression and Functions of Interleukin 18 Receptor on T Helper (Th) Type 1 but not Th2 Cells

1998 ◽  
Vol 188 (8) ◽  
pp. 1485-1492 ◽  
Author(s):  
Damo Xu ◽  
Woon Ling Chan ◽  
Bernard P. Leung ◽  
David Hunter ◽  
Kerstin Schulz ◽  
...  
Keyword(s):  
Th2 Cells ◽  
Interleukin 18 ◽  
T Helper ◽  
Th2 Cell ◽  
A Cell ◽  
Ifn Γ

Interleukin (IL)-18 induces interferon (IFN)-γ synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rβ2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R–derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin–T cell antigen receptor-αβ transgenic mice (D011.10). Anti–IL-18R antibody inhibited IL-18– induced IFN-γ production by Th1 clones in vitro. In vivo, anti–IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-γ and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

scholarly journals Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response.

1993 ◽  
Vol 177 (6) ◽  
pp. 1797-1802 ◽  
Author(s):  
J P Sypek ◽  
C L Chung ◽  
S E Mayor ◽  
J M Subramanyam ◽  
S J Goldman ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Enzyme Linked Immunosorbent Assay ◽  
Th1 Cells ◽  
T Helper ◽  
Ifn Gamma ◽  
Lymph Node Cells ◽  
Helper Type

Resistance to Leishmania major in mice is associated with the appearance of distinct T helper type 1 (Th1) and Th2 subsets. T cells from lymph nodes draining cutaneous lesions of resistant mice are primarily interferon gamma (IFN-gamma)-producing Th1 cells. In contrast, T cells from susceptible mice are principally Th2 cells that generate interleukin 4 (IL-4). Although existing evidence is supportive of a role for IFN-gamma in the generation of Th1 cells, additional factors may be required for a protective response to be maintained. A potential candidate is IL-12, a heterodimeric cytokine produced by monocytes and B cells that has multiple effects on T and natural killer cell function, including inducing IFN-gamma production. Using an experimental leishmanial model we have observed that daily intraperitoneal administration at the time of parasite challenge of either 0.33 micrograms IL-12 (a consecutive 5 d/wk for 5 wk) or 1.0 micrograms IL-12 per mouse (only a consecutive 5 d) caused a > 75% reduction in parasite burden at the site of infection, in highly susceptible BALB/c mice. Delay of treatment by 1 wk had less of a protective effect. Concomitant with these protective effects was an increase in IFN-gamma and a decrease in IL-4 production, as measured by enzyme-linked immunosorbent assay of supernatants generated from popliteal lymph node cells stimulated with leishmanial antigen in vitro. The reduction in parasite numbers induced by IL-12 therapy was still apparent at 10 wk postinfection. In addition, we observed that the administration of a rabbit anti-recombinant murine IL-12 polyclonal antibody (200 micrograms i.p. every other day for 25 d) at the time of infection to resistant C57Bl/6 mice exacerbated disease. These effects were accompanied by a shift in IFN-gamma production in vitro by antigen-stimulated lymph node cells indicative of a Th2-like response. These findings suggest that IL-12 has an important role in initiating a Th1 response and protective immunity.

T-helper type 1 cytokine release is enhanced by in vitro zinc supplementation due to increased natural killer cells

Nutrition ◽  
2007 ◽  
Vol 23 (2) ◽  
pp. 157-163 ◽  
Author(s):  
Claudia H.D. Metz ◽  
Anja K. Schröder ◽  
Silke Overbeck ◽  
Laura Kahmann ◽  
Birgit Plümäkers ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Zinc Supplementation ◽  
Cytokine Release ◽  
T Helper ◽  
Killer Cells ◽  
Type 1 Cytokine ◽  
Helper Type

scholarly journals Antigen-pulsed dendritic cells can efficiently induce an antibody response in vivo.

1992 ◽  
Vol 175 (1) ◽  
pp. 15-21 ◽  
Author(s):  
T Sornasse ◽  
V Flamand ◽  
G De Becker ◽  
H Bazin ◽  
F Tielemans ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antibody Response ◽  
Interleukin 2 ◽  
Humoral Response ◽  
T Helper ◽  
Pulsed Dc ◽  
Immunization Procedure

The aim of this study was to develop an immunization procedure avoiding external adjuvant. Data are presented showing that syngeneic dendritic cells (DC), which have been pulsed in vitro with antigen, induce a strong antibody response in mice. By contrast, antigen (Ag)-pulsed low-density B cells, although equally able to induce interleukin 2 secretion by an Ag-specific T cell hybridoma in vitro, only weakly prime the mice in vivo. Moreover, we show that the injection of Ag-pulsed DC induces the synthesis of isotypes similar to the immunoglobulin classes detected after immunization with the same Ag in complete Freund's adjuvant. Importantly, high amounts of IgG2a antibodies are produced, suggesting that T helper type 1 cells are activated. Collectively, these data indicate that DC can initiate a primary humoral response and that they may be used as physiological adjuvant in vivo.

scholarly journals Mannoprotein from Cryptococcus neoformans Promotes T-Helper Type 1 Anticandidal Responses in Mice

2002 ◽  
Vol 70 (12) ◽  
pp. 6621-6627 ◽  
Author(s):  
Donatella Pietrella ◽  
Rosanna Mazzolla ◽  
Patrizia Lupo ◽  
Lucia Pitzurra ◽  
Maria Jesus Gomez ◽  
...  
Keyword(s):  
T Cells ◽  
Cryptococcus Neoformans ◽  
Delayed Type Hypersensitivity ◽  
Interleukin 12 ◽  
Antigenic Determinants ◽  
T Helper ◽  
Survival Times ◽  
Helper Type

ABSTRACT We previously demonstrated that mannoprotein (MP) from Cryptococcus neoformans (CnMP) stimulates interleukin-12 production by human monocytes, thus fostering a T-helper type 1 (Th1) protective anticryptococcal response. In this paper we show that CnMP was also able to induce a Candida albicans-directed protective Th1 response. This was demonstrated for mice immunized with CnMP by induction of a delayed-type hypersensitivity (DTH) reaction to C. albicans MP (CaMP) as well as induction of gamma interferon production by CD4+ and CD8+ splenic T cells stimulated in vitro with CaMP. CnMP-immunized mice were also partially protected from lethal systemic challenge with C. albicans, as shown by prolonged median survival times and decreased fungal burden in the kidney. Much evidence supports the validity of these cross-reactive and functional Th1 responses: (i) a non-cross-reactive C. albicans antigen, such as enolase, did not produce a DTH response to CaMP; (ii) passive adoptive transfer of T cells primed with CnMP induced a DTH reaction; (iii) C. neoformans extract elicited a DTH response to CaMP; and (iv) a monoclonal antibody (7H6) directed against a major and immunodominant T-cell-stimulatory 65-kDa MP (MP65) of C. albicans also recognized discrete 100-kDa constituents of C. neoformans extracts, as well as secretory constituents of the fungus. These results suggest the presence of common Th1 antigenic determinants in the mannoproteic material of C. neoformans and C. albicans epitopes, which should be considered in devising common strategies for immunoprophylactic or immunotherapeutic control of the fungi.

scholarly journals Human Mesenchymal Stem Cells Modulate Cellular Immune Response to Islet Antigen Glutamic Acid Decarboxylase in Type 1 Diabetes

2010 ◽  
Vol 95 (8) ◽  
pp. 3788-3797 ◽  
Author(s):  
Maria M. Zanone ◽  
Enrica Favaro ◽  
Ilaria Miceli ◽  
Giorgio Grassi ◽  
Elisa Camussi ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Acid Decarboxylase ◽  
Diabetic Patients ◽  
Human Mscs ◽  
T Helper ◽  
Ifn Γ ◽  
Islet Antigen ◽  
Helper Type

Context: Mesenchymal stem cells (MSCs) exert an immunosuppressive effect on the immune system. However, studies on the immunomodulatory potential of MSCs in type 1 diabetes are lacking. Objective: We aimed to evaluate whether human MSCs may inhibit in vitro pancreatic islet antigen-specific T cell activation in type 1 diabetes. Design: Human MSCs were isolated and characterized. Peripheral blood mononuclear cells (PBMCs) were obtained from nine type 1 diabetic patients at disease onset and 13 healthy control subjects. IFN-γ, IL-10, and IL-4 enzyme-linked immunospot responses of lymphocytes incubated with glutamic acid decarboxylase 65 (GAD65) were investigated in PBMC cultures and PBMC/MSC cocultures. Levels of prostaglandin E2 (PGE2), IFN-γ, IL-4, and IL-10 in supernatants were measured by ELISA. PGE2 inhibition experiments with NS-398 and indomethacin were also performed. Results: Five diabetic patients were identified with a positive PBMC IFN-γ response to GAD65 and negative IL-10 and IL-4 response. PBMC/MSC cocultures resulted in a significant decrease in the number of spots and in detection of IL-4-secreting cells. PGE2 inhibitors abrogated the immune-suppressive effect, indicating an involvement of PGE2 production, and the constitutive production of PGE2 by MSCs was enhanced in PBMC/MSC coculture. Moreover, in GAD-responder patients, GAD-stimulated PBMC/MSC cocultures significantly decreased secretion of IFN-γ and IL-10 and increased secretion of IL-4. Conclusions: These results provide evidence that human MSCs abrogate in vitro a proinflammatory T helper type 1 response to an islet antigenic stimulus in type 1 diabetes. MSCs induce IL-4-producing cells, suggesting a possible switch to an antiinflammatory T helper type 2 signaling of T cells.

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