Human TCR Transgenic Bet v 1-Specific Th1 Cells Suppress the Effector Function of Bet v 1-Specific Th2 Cells

Abstract Background Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 2 (Th2) response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SERPINB10 affects the viability of Th2 cells. Methods Th2 cytokines and serum levels of house dust mite (HDM)-specific IgE in bronchoalveolar lavage fluid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by flow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantified by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in human CD4 T cells with lentivirus. Results Knockdown of SERPINB10 expression significantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specific IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells. Conclusion Our results suggest that SERPINB10 may contribute to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

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Rapid Development of Th2 Activity During T Cell Priming

Clinical and Developmental Immunology ◽

10.1080/10446670310001598537 ◽

2003 ◽

Vol 10 (1) ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Adam F. Cunningham ◽

Kai-Michael Toellner

Keyword(s):

T Cells ◽

T Cell ◽

Rapid Development ◽

Critical Role ◽

Cell Polarization ◽

Th2 Cells ◽

Th1 Cells ◽

T Helper ◽

Th 1 ◽

Th1 And Th2

The paradigm of T helper-1 (Th-1) and Th-2 cells developing from non-committed naïve precursors is firmly established. Th1 cells are characterized by IFN production and, in mice, the selective switching to IgG2a. Conversely IL-4 production and selective switching to IgG1 and IgE characterize Th2 cells. Analysis of Th2 inductionin vitroindicates that this polarization develops gradually in T cells activated by anti-CD3 in the presence of IL-4; conversely anti-CD3 and IFN induce Th1 cells. In this report, we explore evidence that indicates that the T helper cell polarizationin vivocannot solely be explained by the cytokine environment. This is provided by studying the early acquisition of Th1 and Th2 activities during responses to a mixture of Th1 and Th2-inducing antigens. It is shown that these divergent forms of T cell help can rapidly develop in cells within a single lymph node. It is argued that early polarization to show Th-1 or Th-2 behavior can be induced by signals delivered during cognate interaction between virgin T cells and dendritic cells, in the absence of type 1 or type 2 cytokines. This contrasts with the critical role of the cytokines in reinforcing the Th-phenotype and selectively expanding T helper clones.

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ICOS Expression by Activated Human Th Cells Is Enhanced by IL-12 and IL-23: Increased ICOS Expression Enhances the Effector Function of Both Th1 and Th2 Cells

The Journal of Immunology ◽

10.4049/jimmunol.173.3.1779 ◽

2004 ◽

Vol 173 (3) ◽

pp. 1779-1786 ◽

Cited By ~ 31

Author(s):

Lianne Wassink ◽

Pedro L. Vieira ◽

Hermelijn H. Smits ◽

Gillian A. Kingsbury ◽

Anthony J. Coyle ◽

...

Keyword(s):

Effector Function ◽

Th2 Cells ◽

Th Cells ◽

Th1 And Th2

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Selective Induction of Th2-Attracting Chemokines CCL17 and CCL22 in Human B Cells by Latent Membrane Protein 1 of Epstein-Barr Virus

Journal of Virology ◽

10.1128/jvi.78.4.1665-1674.2004 ◽

2004 ◽

Vol 78 (4) ◽

pp. 1665-1674 ◽

Cited By ~ 106

Author(s):

Takashi Nakayama ◽

Kunio Hieshima ◽

Daisuke Nagakubo ◽

Emiko Sato ◽

Masahiro Nakayama ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

Epstein Barr Virus ◽

Cytotoxic T Cells ◽

Th2 Cells ◽

Th1 Cells ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

ABSTRACT Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-κB pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-κB sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-κB and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.

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

Journal of Experimental Medicine ◽

10.1084/jem.20031368 ◽

2004 ◽

Vol 199 (4) ◽

pp. 535-545 ◽

Cited By ~ 86

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.

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T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription

Journal of Experimental Medicine ◽

10.1084/jem.20052165 ◽

2006 ◽

Vol 203 (3) ◽

pp. 755-766 ◽

Cited By ~ 213

Author(s):

Takashi Usui ◽

Jan C. Preiss ◽

Yuka Kanno ◽

Zheng Ju Yao ◽

Jay H. Bream ◽

...

Keyword(s):

Early Stage ◽

Th2 Cells ◽

Th1 Cells ◽

T Helper ◽

Down Regulation ◽

Ifng Gene ◽

Deoxyribonuclease I ◽

Negative Effect ◽

Th2 Differentiation

T helper type 1 (Th1) development is facilitated by interrelated changes in key intracellular factors, particularly signal transducer and activator of transcription (STAT)4, T-bet, and GATA-3. Here we show that CD4+ cells from T-bet−/− mice are skewed toward Th2 differentiation by high endogenous GATA-3 levels but exhibit virtually normal Th1 differentiation provided that GATA-3 levels are regulated at an early stage by anti–interleukin (IL)-4 blockade of IL-4 receptor (R) signaling. In addition, under these conditions, Th1 cells from T-bet−/− mice manifest IFNG promotor accessibility as detected by histone acetylation and deoxyribonuclease I hypersensitivity. In related studies, we show that the negative effect of GATA-3 on Th1 differentiation in T-bet−/− cells arises from its ability to suppress STAT4 levels, because if this is prevented by a STAT4-expressing retrovirus, normal Th1 differentiation is observed. Finally, we show that retroviral T-bet expression in developing and established Th2 cells leads to down-regulation of GATA-3 levels. These findings lead to a model of T cell differentiation that holds that naive T cells tend toward Th2 differentiation through induction of GATA-3 and subsequent down-regulation of STAT4/IL-12Rβ2 chain unless GATA-3 levels or function is regulated by T-bet. Thus, the principal function of T-bet in developing Th1 cells is to negatively regulate GATA-3 rather than to positively regulate the IFNG gene.

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Encephalitogenic Th1 cells are inhibited by Th2 cells with related peptide specificity: Relative roles of interleukin (IL)-4 and IL-10

Journal of Neuroimmunology ◽

10.1016/0165-5728(93)90194-4 ◽

1993 ◽

Vol 48 (2) ◽

pp. 213-220 ◽

Cited By ~ 71

Author(s):

Roel C. van der Veen ◽

Stephen A. Stohlman

Keyword(s):

Th2 Cells ◽

Th1 Cells ◽

Peptide Specificity ◽

Related Peptide

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ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells

Blood ◽

10.1182/blood-2013-10-535245 ◽

2014 ◽

Vol 124 (7) ◽

pp. 1070-1080 ◽

Cited By ~ 166

Author(s):

Sonia Guedan ◽

Xi Chen ◽

Aviv Madar ◽

Carmine Carpenito ◽

Shannon E. McGettigan ◽

...

Keyword(s):

T Cells ◽

Effector Function ◽

Th1 Cells ◽

Antigen Receptors ◽

Chimeric Antigen Receptors ◽

Effector Functions ◽

Key Points

Key Points ICOS-based CARs program bipolar TH17/TH1 cells with augmented effector function and in vivo persistence. The expression of selected CAR endodomains can program T cells for their subsequent differentiation fates and effector functions.

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Limited expression of R5-tropic HIV-1 in CCR5-positive type 1–polarized T cells explained by their ability to produce RANTES, MIP-1α, and MIP-1β

Blood ◽

10.1182/blood.v95.4.1167.004k11_1167_1174 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1167-1174 ◽

Cited By ~ 37

Author(s):

Francesco Annunziato ◽

Grazia Galli ◽

Filomena Nappi ◽

Lorenzo Cosmi ◽

Roberto Manetti ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

Receptor Expression ◽

Th2 Cells ◽

Th1 Cells ◽

Naive T Cells ◽

Naïve T Cells ◽

Viral Spread ◽

Hiv 1

Human T helper (Th) cells (Th1- or Th2-oriented memory T cells as well as Th1- or Th2-polarized naive T cells) were infected in vitro with an R5-tropic HIV-1 strain (BaL) and assessed for their profile of cytokine production, CCR5 receptor expression, and HIV-1 p24 antigen (p24 Ag) production. Higher p24 Ag production was found in CCR5-negative Th2-like memory T cells than in CCR5-positive Th1-like memory T cells. By contrast, p24 Ag production was higher in Th1-polarized activated naive T cells in the first 4 days after infection. However, p24 Ag production in Th1-polarized T cells became comparable or even lower than the production in Th2-polarized populations later in infection or when the cells were infected with HIV-1BaL after secondary stimulation. The higher levels of p24 Ag production by Th1-polarized naive T cells soon after infection reflected a higher virus entry, as assessed by the single round infection assay using the HIV–chloramphenicol acetyl transferase (HIV-CAT) R5-tropic virus that contains the envelope protein of HIV-1 YU2 strain. The limitation of viral spread in the Th1-polarized populations, despite the initial higher level of T-cell entry of R5-tropic strains, was due to the ability of Th1 cells to produce greater amounts of β-chemokines than Th2 cells. In fact, an inverse correlation was observed between Th1-polarized naive T cells and Th1-like memory-activated T cells in regards to p24 Ag production and the release of the following CCR5-binding chemokines: regulated on activation normal T expressed and secreted (RANTES), macrophage inflammatory protein–1 (MIP-1), and MIP-1β. Moreover, infection with the HIV-1BaL strain of Th1-polarized T cells in the presence of a mixture of anti-RANTES, anti–MIP-1, and anti–MIP-1β neutralizing antibodies resulted in a significant increase of HIV-1 expression. These findings suggest that Th1-type responses may favor CD4+ T-cell infection by R5-tropic HIV-1 strains, but HIV-1 spread in Th1 cells is limited by their ability to produce CCR5-binding chemokines.

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