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 A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

1998 ◽  
Vol 188 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
Mark H. Kaplan ◽  
Andrea L. Wurster ◽  
Michael J. Grusby
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Signal Transducer ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

scholarly journals Distinct Role of Antigen-Specific T Helper Type 1 (Th1) and Th2 Cells in Tumor Eradication in Vivo

1999 ◽  
Vol 190 (5) ◽  
pp. 617-628 ◽  
Author(s):  
Takashi Nishimura ◽  
Kenji Iwakabe ◽  
Masashi Sekimoto ◽  
Yasushi Ohmi ◽  
Takashi Yahata ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Th2 Cells ◽  
T Helper ◽  
Th1 Cell ◽  
Th2 Cell ◽  
Tumor Eradication ◽  
Th1 And Th2

The role of T helper type 1 (Th1) and Th2 cells in tumor immunity was investigated using Th cells induced from ovalbumin (OVA)-specific T cell receptor transgenic mice. Although Th1 cells exhibited stronger cytotoxicity than Th2 cells, both cell types completely eradicated tumors when transferred into mice bearing A20 tumor cells transfected with the OVA gene (A20-OVA). Th1 cells eradicated the tumor mass by inducing cellular immunity, whereas Th2 cells destroyed the tumor by inducing tumor necrosis. Both Th1 and Th2 cells required CD8+ T cells to eliminate tumors, and neither of these cells were able to completely eliminate A20-OVA tumors from T and B cell–deficient RAG2−/− mice. Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8+ cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy. Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1–dependent cell–cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy. These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.

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 Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells

2002 ◽  
Vol 196 (7) ◽  
pp. 969-977 ◽  
Author(s):  
Andrea L. Wurster ◽  
Vikki L. Rodgers ◽  
Abhay R. Satoskar ◽  
Matthew J. Whitters ◽  
Deborah A. Young ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Th2 Response ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The cytokine potential of developing T helper (Th) cells is directly shaped both positively and negatively by the cytokines expressed by the effector Th cell subsets. Here we find that the recently identified cytokine, interleukin (IL)-21, is preferentially expressed by Th2 cells when compared with Th1 cells generated in vitro and in vivo. Exposure of naive Th precursors to IL-21 inhibits interferon (IFN)-γ production from developing Th1 cells. The repression of IFN-γ production is specific in that the expression of other Th1 and Th2 cytokines is unaffected. IL-21 decreases the IL-12 responsiveness of developing Th cells by specifically reducing both signal transducer and activator of transcription 4 protein and mRNA expression. These results suggest that Th2 cell-derived IL-21 regulates the development of IFN-γ–producing Th1 cells which could serve to amplify a Th2 response.

scholarly journals Dendritic Cells Discriminate between Yeasts and Hyphae of the Fungus Candida albicans

2000 ◽  
Vol 191 (10) ◽  
pp. 1661-1674 ◽  
Author(s):  
Cristiana Fè d'Ostiani ◽  
Giuseppe Del Sero ◽  
Angela Bacci ◽  
Claudia Montagnoli ◽  
Antonio Spreca ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Candida Albicans ◽  
Ex Vivo ◽  
T Helper ◽  
Myeloid Dendritic Cells ◽  
Mucosal Surfaces ◽  
A Cell

The fungus Candida albicans behaves as a commensal as well as a true pathogen of areas highly enriched in dendritic cells, such as skin and mucosal surfaces. The ability of the fungus to reversibly switch between unicellular yeast to filamentous forms is thought to be important for virulence. However, whether it is the yeast or the hyphal form that is responsible for pathogenicity is still a matter of debate. Here we show the interaction, and consequences, of different forms of C. albicans with dendritic cells. Immature myeloid dendritic cells rapidly and efficiently phagocytosed both yeasts and hyphae of the fungus. Phagocytosis occurred through different phagocytic morphologies and receptors, resulting in phagosome formation. However, hyphae escaped the phagosome and were found lying free in the cytoplasm of the cells. In vitro, ingestion of yeasts activated dendritic cells for interleukin (IL)-12 production and priming of T helper type 1 (Th1) cells, whereas ingestion of hyphae inhibited IL-12 and Th1 priming, and induced IL-4 production. In vivo, generation of antifungal protective immunity was induced upon injection of dendritic cells ex vivo pulsed with Candida yeasts but not hyphae. The immunization capacity of yeast-pulsed dendritic cells was lost in the absence of IL-12, whereas that of hypha-pulsed dendritic cells was gained in the absence of IL-4. These results indicate that dendritic cells fulfill the requirement of a cell uniquely capable of sensing the two forms of C. albicans in terms of type of immune responses elicited. By the discriminative production of IL-12 and IL-4 in response to the nonvirulent and virulent forms of the fungus, dendritic cells appear to meet the challenge of Th priming and education in C. albicans saprophytism and infections.

scholarly journals Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

1994 ◽  
Vol 179 (4) ◽  
pp. 1273-1283 ◽  
Author(s):  
R Manetti ◽  
F Gerosa ◽  
M G Giudizi ◽  
R Biagiotti ◽  
P Parronchi ◽  
...  
Keyword(s):  
T Cells ◽  
Interferon Gamma ◽  
Specific Antigen ◽  
Th2 Cells ◽  
Interleukin 12 ◽  
T Helper ◽  
Ifn Gamma ◽  
Selection Of

Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

scholarly journals Interleukin 18 Acts on Memory T Helper Cells Type 1 to Induce Airway Inflammation and Hyperresponsiveness in a Naive Host Mouse

2004 ◽  
Vol 199 (4) ◽  
pp. 535-545 ◽  
Author(s):  
Takaaki Sugimoto ◽  
Yuriko Ishikawa ◽  
Tomohiro Yoshimoto ◽  
Nobuki Hayashi ◽  
Jiro Fujimoto ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Bronchial Asthma ◽  
Allergic Diseases ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Inflammatory Protein ◽  
Ifn Γ ◽  
Factor Α

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-γ production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-γ–expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-γ–expressing Th1 cells, both of which express IL-18 receptor α chain strongly, produce IFN-γ, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor α, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1α upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.

Experimental silicosis: a shift to a preferential IFN-γ-based Th1 response in thoracic lymph nodes

2000 ◽  
Vol 278 (6) ◽  
pp. L1221-L1230 ◽  
Author(s):  
Holger Garn ◽  
Anke Friedetzky ◽  
Andrea Kirchner ◽  
Ruth Jäger ◽  
Diethard Gemsa
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cell ◽  
Mrna Levels ◽  
Ifn Γ

In chronic silicosis, mechanisms leading to lymphocyte activation are still poorly understood, although it is well known that not only the lung but also the draining lymph nodes are affected. In the present study, we investigated T-cell activation by analysis of cytokine expression in the enlarged thoracic lymph nodes of rats 2 mo after an 8-day silica aerosol exposure. In the case of helper T cell (Th) type 1 cytokines, we found a significant increase in interferon (IFN)-γ mRNA expression, whereas interleukin (IL)-2 expression remained unchanged. In contrast, gene transcription for the Th2-type cytokines IL-4 and IL-10 was diminished. In addition, with use of an in vitro lymphocyte-macrophage coculture system, an enhanced IFN-γ and a reduced IL-10 release were shown with cells from silicotic animals. With regard to IFN-γ-inducing cytokines, we observed enhanced IL-12 mRNA levels in vivo, whereas IL-18 gene expression was slightly decreased. These data indicate that a persistent shift toward an IFN-γ-dominated type 1 (Th1/cytotoxic T cell type 1) T-cell reaction pattern occurred within the thoracic lymph nodes of silicotic animals. Thus a mutual activation of lymphocytes and macrophages may maintain the chronic inflammatory changes that characterize silicosis.

scholarly journals T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

2016 ◽  
Vol 113 (5) ◽  
pp. E568-E576 ◽  
Author(s):  
Jimena Perez-Lloret ◽  
Isobel S. Okoye ◽  
Riccardo Guidi ◽  
Yashaswini Kannan ◽  
Stephanie M. Coomes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Allergic Diseases ◽  
Treg Cells ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Cytokines And Chemokines ◽  
Th2 Cell

There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ+CD4+ T-helper 2 (TH2) cells orchestrate the type-2–driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081–E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4gfp+αβ+CD4+ TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell–intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24−/− T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1–regulated signaling. Following this prediction, we found that Trim24−/− T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β–mediated activation in vitro and in vivo, and fail to respond to IL-1β–exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell–intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.

scholarly journals Cc Chemokine Receptor (Ccr)3/Eotaxin Is Followed by Ccr4/Monocyte-Derived Chemokine in Mediating Pulmonary T Helper Lymphocyte Type 2 Recruitment after Serial Antigen Challenge in Vivo

2000 ◽  
Vol 191 (2) ◽  
pp. 265-274 ◽  
Author(s):  
Clare M. Lloyd ◽  
Tracy Delaney ◽  
Trang Nguyen ◽  
Jane Tian ◽  
Carlos Martinez-A ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Progressive Increase ◽  
Allergic Airway Disease ◽  
Antigen Challenge ◽  
Th2 Cells ◽  
T Helper ◽  
Cc Chemokine

Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises when the in vivo significance of this distinct expression is discussed. To address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo recruitment of Th2 cells, we have transferred effector Th cells into naive mice to induce allergic airway disease. Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells. We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.

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