scholarly journals Costimulation through B7-2 (CD86) Is Required for the Induction of a Lung Mucosal T Helper Cell 2 (TH2) Immune Response and Altered Airway Responsiveness

1997 ◽  
Vol 185 (9) ◽  
pp. 1671-1680 ◽  
Author(s):  
Shogo Tsuyuki ◽  
Junko Tsuyuki ◽  
Karin Einsle ◽  
Manfred Kopf ◽  
Anthony J. Coyle
Keyword(s):  
Immune Response ◽  
Allergen Exposure ◽  
T Helper Cell ◽  
Helper Cell ◽  
Eosinophil Infiltration ◽  
T Helper ◽  
Th2 Cytokine ◽  
Th2 Immune Response ◽  
Eosinophil Accumulation

The recruitment of eosinophils into the airways after allergen exposure is dependent on interleukin (IL) 5 secreted from antigen-specific CD4+ T cells of the T helper cell (Th) 2 subset. However, while it is established that costimulation through CD28 is required for TCR-mediated activation and IL-2 production, the importance of this mechanism for the induction of a Th2 immune response is less clear. In the present study, we administered the fusion protein CTLA-4 immunoglobulin (Ig) into the lungs before allergen provocation to determine whether CD28/CTLA-4 ligands are required for allergen-induced eosinophil accumulation and the production of Th2 cytokines. Administration of CTLA-4 Ig inhibited the recruitment of eosinophils into the lungs by 75% and suppressed IgE in the bronchoalveolar lavage fluid. CTLA-4 Ig also inhibited the production of IL-4, IL-5, and IL-10 by 70–80% and enhanced interferon-γ production from CD3–T cell receptor–activated lung Thy1.2+ cells. Allergen exposure upregulated expression of B7-2, but not B7-1, on B cells from the lung within 24 h. Moreover, airway administration of an anti-B7-2 monoclonal antibody (mAb) inhibited eosinophil infiltration, IgE production, and Th2 cytokine secretion comparable in magnitude to that observed with CTLA-4 Ig. Treatment with an anti-B7-1 mAb had a small, but significant effect on eosinophil accumulation, although was less effective in inhibiting Th2 cytokine production. The anti-B7-2, but not anti-B7-1, mAb also inhibited antigen-induced airway hyperresponsiveness in vivo. In all of the parameters assessed, the combination of both the anti-B7-1 and anti-B7-2 mAb was no more effective than anti-B7-2 mAb treatment alone. We propose that strategies aimed at inhibition of CD28 interactions with B7-2 molecules may represent a novel therapeutic target for the treatment of lung mucosal allergic inflammation.

scholarly journals T helper cell polarisation as a measure of the maturation of the immune response

2003 ◽  
Vol 12 (5) ◽  
pp. 285-292 ◽  
Author(s):  
Scott B. Cameron ◽  
Ellen H. Stolte ◽  
Anthony W. Chow ◽  
Huub F. J. Savelkoul
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Intracellular Cytokine Staining ◽  
T Helper Cell ◽  
Helper Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intracellular Cytokine ◽  
T Helper

Background:T helper cell polarisation is important under chronic immune stimulatory conditions and drives the type of the evolving immune response. Mice treated with superantigensin vivodisplay strong effects on Thsubset differentiation. The aim of the study was to detect the intrinsic capacity of T cells to polarise under variousex vivoconditions.Methods:Purified CD4+T cells obtained from superantigen-treated mice were cultured under Thpolarising conditionsin vitro. By combining intracellular cytokine staining and subsequent flow cytometric analysis with quantitative cytokine measurements in culture supernatants by enzyme-linked immunosorbent assay (ELISA), the differential Thpolarising capacity of the treatment can be detected in a qualitative and quantitative manner.Results and conclusions:BALB/c mice were shown to be biased to develop strong Th2 polarised immune responses using Th0 stimulation of purified CD4+T cells from phosphate-buffered saline-treated mice. Nevertheless, our analysis methodology convincingly showed that even in these mice, Toxic Shock Syndrome Toxin-1 treatmentin vivoresulted in a significantly stronger Th1 polarising effect than control treatment. Our results indicate that populations of Thcells can be assessed individually for their differential Th1 or Th2 maturation capacityin vivoby analysing robustin vitropolarisation cultures combined with intracellular cytokine staining and ELISA.

scholarly journals The Increasing Prevalence of Crohn’s Disease in Industrialized Societies: The Price of Progress?

2005 ◽  
Vol 19 (2) ◽  
pp. 89-95 ◽  
Author(s):  
Ron W Wells ◽  
Michael G Blennerhassett
Keyword(s):  
Immune Response ◽  
Crohn’S Disease ◽  
Immune System ◽  
Crohn's Disease ◽  
T Helper Cell ◽  
Helper Cell ◽  
Cell Type ◽  
T Helper ◽  
Th2 Immune Response ◽  
Helper Cell Type

Crohn’s disease (CD) is an idiopathic inflammatory condition of the gastrointestinal system. While inflammation can activate one of a number of specific branches of the immune system, CD promotes a T helper cell type 1 (Th1) profile. The prospect that CD is a form of Th1-dominant autoimmune disease is gaining acceptance, with support from the current use of immunosuppressants. Recently, convincing evidence that the various branches of the immune system have the ability to keep each other in check has suggested that the Th1 profile of CD may stem from a greatly reduced T helper cell type 2 (Th2) immune response. A strong Th2 immune response is a characteristic of the once prevalent enteric parasitic diseases, now nearly eradicated from industrial society. This has led to the acceptance of a hygiene hypothesis, which suggests that the inverse relationship between CD and the level of a society’s industrialization is, in fact, causal -- that the lack of parasitic infections causes a weakened systemic Th2 cytokine profile, leading to elevated Th1 cytokines and, ultimately, the development of spontaneous Th1-mediated diseases such as CD. Supporting this, it has been recently demonstrated that an experimentally-induced Th2 response can help moderate Th1-dominant events in both animal and human studies. Based on this recent and convincing work, the present review focuses on the role of immunoregulation in the development of CD, with particular emphasis on the potential use of Th2-promoting agents (such as helminths or cytokines) as therapeutics in the treatment or prevention of CD.

scholarly journals Crucial Role of the Interleukin 1 Receptor Family Member T1/St2 in T Helper Cell Type 2–Mediated Lung Mucosal Immune Responses

1999 ◽  
Vol 190 (7) ◽  
pp. 895-902 ◽  
Author(s):  
Anthony J. Coyle ◽  
Clare Lloyd ◽  
Jane Tian ◽  
Trang Nguyen ◽  
Christina Erikkson ◽  
...  
Keyword(s):  
Immune Responses ◽  
T Helper Cell ◽  
Helper Cell ◽  
Eosinophil Infiltration ◽  
Cell Type ◽  
T Helper ◽  
Helper Cell Type ◽  
Mucosal Immune Responses

T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.

scholarly journals Regulation and Function of the Interleukin 13 Receptor α 2 During a T Helper Cell Type 2–dominant Immune Response

2003 ◽  
Vol 197 (6) ◽  
pp. 687-701 ◽  
Author(s):  
Monica G. Chiaramonte ◽  
Margaret Mentink-Kane ◽  
Bruce A. Jacobson ◽  
Allen W. Cheever ◽  
Matthew J. Whitters ◽  
...  
Keyword(s):  
Immune Response ◽  
Airway Hyperreactivity ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper ◽  
Fibrotic Response ◽  
Tissue Eosinophilia ◽  
Nematode Parasites ◽  
Deficient Mice

Highly polarized type 2 cytokine responses can be harmful and even lethal to the host if they are too vigorous or persist too long. Therefore, it is important to elucidate the mechanisms that down-regulate these reactions. Interleukin (IL)-13 has emerged as a central mediator of T helper cell (Th)2-dominant immune responses, exhibiting a diverse array of functional activities including regulation of airway hyperreactivity, resistance to nematode parasites, and tissue remodeling and fibrosis. Here, we show that IL-13 receptor (R)α2 is a critical down-regulatory factor of IL-13–mediated tissue fibrosis induced by the parasitic helminth Schistosoma mansoni. IL-13Rα2 expression was induced after the onset of the fibrotic response, IL-10, IL-13, and Stat6 dependent, and inhibited by the Th1-inducing adjuvant IL-12. Strikingly, schistosome-infected C57BL/6 and BALB/c IL-13Rα2–deficient mice showed a marked exacerbation in hepatic fibrosis, despite displaying no change in granuloma size, tissue eosinophilia, or mastocytosis. Fibrosis increased despite the fact that IL-13 levels decreased significantly in the liver and serum. Importantly, pathology was prevented when IL-13Rα2–deficient mice were treated with a soluble IL-13Rα2-Fc construct, formally demonstrating that their exacerbated fibrotic response was due to heightened IL-13 activity. Together, these studies illustrate the central role played by the IL-13Rα2 in the down-regulation of a chronic and pathogenic Th2-mediated immune response.

scholarly journals c-maf Promotes T Helper Cell Type 2 (Th2) and Attenuates Th1 Differentiation by Both Interleukin 4–dependent and –independent Mechanisms

1998 ◽  
Vol 188 (10) ◽  
pp. 1859-1866 ◽  
Author(s):  
I-Cheng Ho ◽  
David Lo ◽  
Laurie H. Glimcher
Keyword(s):  
Transgenic Mice ◽  
Ectopic Expression ◽  
T Helper Cell ◽  
Helper Cell ◽  
Th2 Cytokines ◽  
Cell Type ◽  
T Helper ◽  
Helper Cell Type

The c-maf protooncogene is a T helper cell type 2 (Th2)-specific transcription factor that activates the interleukin (IL)-4 promoter in vitro. Although it has been postulated that c-maf directs the Th2-specific expression of the IL-4 gene in vivo, direct evidence that c-maf functions during the differentiation of normal, primary T cells is lacking. We now demonstrate that overexpression of c-maf in vivo skews the Th immune response along a Th2 pathway, as evidenced by increased production of Th2 cytokines and the IL-4–dependent immunoglobulins, IgG1 and IgE. The overproduction of IgGl and IgE in the CD4 promoter/c-maf transgenic mice was IL-4 dependent since this was not observed in c-maf transgenic mice bred onto an IL-4–deficient background. Ectopic expression of c-maf in mature Th1 cells did not confer on them the ability to produce IL-4, but did decrease the production of IFN-γ. The attenuation of Th1 differentiation by c-maf overexpression occurred by a mechanism that was independent of IL-4 and other Th2 cytokines, and could be overcome by IL-12. These studies demonstrate that c-maf promotes Th2 differentiation by IL-4–dependent mechanisms and attenuates Th1 differentiation by Th2 cytokine-independent mechanisms.

scholarly journals CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo

2003 ◽  
Vol 198 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Guillaume Oldenhove ◽  
Magali de Heusch ◽  
Georgette Urbain-Vansanten ◽  
Jacques Urbain ◽  
Charlie Maliszewski ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Peripheral Tolerance ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II–restricted interferon γ–producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.

scholarly journals ITAM signaling in dendritic cells controls T helper cell priming by regulating MHC class II recycling

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3208-3218 ◽  
Author(s):  
Daniel B. Graham ◽  
Holly M. Akilesh ◽  
Grzegorz B. Gmyrek ◽  
Laura Piccio ◽  
Susan Gilfillan ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Autoimmune Encephalitis ◽  
Class Ii ◽  
T Helper Cell ◽  
Helper Cell ◽  
Nucleotide Exchange ◽  
T Helper

Abstract Immature dendritic cells (DCs) specialize in antigen capture and maintain a highly dynamic pool of intracellular major histocompatibility complex class II (MHCII) that continuously recycles from peptide loading compartments to the plasma membrane and back again. This process facilitates sampling of environmental antigens for presentation to T helper cells. Here, we show that a signaling pathway mediated by the DC immunoreceptor tyrosine-based activation motif (ITAM)–containing adaptors (DAP12 and FcRγ) and Vav family guanine nucleotide exchange factors controls the half-life of surface peptide-MHCII (pMHCII) complexes and is critical for CD4 T-cell triggering in vitro. Strikingly, mice with disrupted DC ITAMs show defective T helper cell priming in vivo and are protected from experimental autoimmune encephalitis. Mechanistically, we show that deficiency in ITAM signaling results in increased pMHCII internalization, impaired recycling, and an accumulation of ubiquitinated MHCII species that are prematurely degraded in lysosomes. We propose a novel mechanism for control of T helper cell priming.

scholarly journals The IRE1a-XBP1 pathway promotes T helper cell differentiation by resolving secretory stress and accelerating proliferation

2017 ◽  
Author(s):  
Jhuma Pramanik ◽  
Xi Chen ◽  
Gozde Kar ◽  
Tomás Gomes ◽  
Johan Henriksson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Lymphocyte Activation ◽  
Cell Types ◽  
T Helper Cell ◽  
Helper Cell ◽  
Secretory Cells ◽  
T Helper ◽  
Sequencing Data

SummaryThe IRE1a-XBP1 pathway, a conserved adaptive mediator of the unfolded protein response, is indispensable for the development of secretory cells. It maintains endoplasmic reticulum homeostasis by facilitating protein folding and enhancing secretory capacity of the cells. Its role in immune cells is emerging. It is involved in dendritic cell, plasma cell and eosinophil development and differentiation. Using genome-wide approaches, integrating ChIPmentation and mRNA-sequencing data, we have elucidated the regulatory circuitry governed by the IRE1a-XBP1 pathway in type-2 T helper cells (Th2). We show that the XBP1 transcription factor is activated by splicing in vivo in T helper cell lineages. We report a comprehensive repertoire of XBP1 target genes in Th2 lymphocytes. We found that the pathway is conserved across cell types in terms of resolving secretory stress, and has T helper cell-specific functions in controlling activation-dependent Th2 cell proliferation and regulating cytokine expression in addition to secretion. These results provide a detailed picture of the regulatory map governed by the XBP1 transcription factor during Th2 lymphocyte activation.

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