Production of Both IL-27 and IFN-γ after the Treatment with a Ligand for Invariant NK T Cells Is Responsible for the Suppression of Th2 Response and Allergic Inflammation in a Mouse Experimental Asthma Model

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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Loss of IFN-γ Production by Invariant NK T Cells in Advanced Cancer

The Journal of Immunology ◽

10.4049/jimmunol.167.7.4046 ◽

2001 ◽

Vol 167 (7) ◽

pp. 4046-4050 ◽

Cited By ~ 266

Author(s):

Syed Muhammad Ali Tahir ◽

Olivia Cheng ◽

Angela Shaulov ◽

Yasuhiko Koezuka ◽

Glenn J. Bubley ◽

...

Keyword(s):

T Cells ◽

Advanced Cancer ◽

Nk T Cells ◽

Ifn Γ

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Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis

Journal of Clinical Investigation ◽

10.1172/jci19836 ◽

2004 ◽

Vol 113 (10) ◽

pp. 1490-1497 ◽

Cited By ~ 466

Author(s):

Ivan J. Fuss ◽

Frank Heller ◽

Monica Boirivant ◽

Francisco Leon ◽

Masaru Yoshida ◽

...

Keyword(s):

Ulcerative Colitis ◽

T Cells ◽

Th2 Response ◽

Nk T Cells

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NK T Cells Contribute to Expansion of CD8+ T Cells and Amplification of Antiviral Immune Responses to Respiratory Syncytial Virus

Journal of Virology ◽

10.1128/jvi.76.9.4294-4303.2002 ◽

2002 ◽

Vol 76 (9) ◽

pp. 4294-4303 ◽

Cited By ~ 130

Author(s):

Teresa R. Johnson ◽

Seokmann Hong ◽

Luc Van Kaer ◽

Yasuhiko Koezuka ◽

Barney S. Graham

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

T Lymphocytes ◽

Immune Responses ◽

Natural Killer ◽

Viral Clearance ◽

Normal Numbers ◽

Nk T Cells ◽

Ifn Γ ◽

Syncytial Virus

ABSTRACT CD1d-deficient mice have normal numbers of T lymphocytes and natural killer cells but lack Vα14+ natural killer T cells. Respiratory syncytial virus (RSV) immunopathogenesis was evaluated in 129×C57BL/6, C57BL/6, and BALB/c CD1d−/− mice. CD8+ T lymphocytes were reduced in CD1d−/− mice of all strains, as shown by cell surface staining and major histocompatibility complex class I tetramer analysis, and resulted in strain-specific alterations in illness, viral clearance, and gamma interferon (IFN-γ) production. Transient activation of NK T cells in CD1d+/+ mice by α-GalCer resulted in reduced illness and delayed viral clearance. These data suggest that early IFN-γ production and efficient induction of CD8+-T-cell responses during primary RSV infection require CD1d-dependent events. We also tested the ability of α-GalCer as an adjuvant to modulate the type 2 immune responses induced by RSV glycoprotein G or formalin-inactivated RSV immunization. However, immunized CD1-deficient or α-GalCer-treated wild-type mice did not exhibit diminished disease following RSV challenge. Rather, some disease parameters, including cytokine production, eosinophilia, and viral clearance, were increased. These findings indicate that CD1d-dependent NK T cells play a role in expansion of CD8+ T cells and amplification of antiviral responses to RSV.

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Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS

Multiple Sclerosis Journal ◽

10.1177/135245850100700401 ◽

2001 ◽

Vol 7 (4) ◽

pp. 209-219 ◽

Cited By ~ 72

Author(s):

M Chen ◽

B Gran ◽

K Costello ◽

K Johnson ◽

R Martin ◽

...

Keyword(s):

T Cells ◽

Glatiramer Acetate ◽

Mechanism Of Action ◽

Th2 Response ◽

Partial Agonists ◽

Th2 Cytokine ◽

Ifn Γ ◽

Pre Treatment ◽

T Cell Lines ◽

Th1 And Th2 Responses

Glatiramer acetate (GA) is an approved treatment for multiple sclerosis (MS). The proposed mechanism of action is the induction of GA-specific T cells characterized by protective anti-inflammatory Th2 response. We tested this hypothesis in 11 MS patients treated with GA from 1-19 months. Interferon-g and IL-5 (markers of Th1 and Th2 responses respectively) were assayed by ELISA in GA-specific T-cell lines (TCL) supernatants. Th1/Th2 bias was defined based on the ratio of IFN-γ/IL-5 secretion. Fifty-eight pre-treatment, and 75 on-treatment GA-specific TCL were generated. On-treatment mean IL-5 levels in GA-TCL increased significantly, whereas those for IFN-g were markedly reduced. Consequently, the ratio of IFN-γ/IL-5 also shifted in favor of a Th2 response. The percentage of GA-TCL classified as Th1 was decreased, whereas those classified as Th2 increased on-treatment as compared to pre-treatment. Some GA-specific TCL, (approximately 25%) generated during treatment secreted predominantly IL-5 in response to MBP and the immunodominant MBP peptide 83-99, indicating that these crossreactive antigens can act as partial agonists for GA-reactive TCL. These results strongly suggest that the mechanism of action of GA in MS involves the induction of crossreactive GA-specific T cells with a predominant Th2 cytokine profile.

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Constitutive Cytokine mRNAs Mark Natural Killer (NK) and NK T Cells Poised for Rapid Effector Function

Journal of Experimental Medicine ◽

10.1084/jem.20030630 ◽

2003 ◽

Vol 198 (7) ◽

pp. 1069-1076 ◽

Cited By ~ 436

Author(s):

Daniel B. Stetson ◽

Markus Mohrs ◽

R. Lee Reinhardt ◽

Jody L. Baron ◽

Zhi-En Wang ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Natural Killer ◽

Thymic Development ◽

Evolutionary Selection ◽

Nk T Cells ◽

Ifn Γ ◽

Selection For ◽

Cytokine Mrnas ◽

Developmental Maturation

Natural killer (NK) and NK T cells are tissue lymphocytes that secrete cytokines rapidly upon stimulation. Here, we show that these cells maintain distinct patterns of constitutive cytokine mRNAs. Unlike conventional T cells, NK T cells activate interleukin (IL)-4 and interferon (IFN)-γ transcription during thymic development and populate the periphery with both cytokine loci previously modified by histone acetylation. Similarly, NK cells transcribe and modify the IFN-γ gene, but not IL-4, during developmental maturation in the bone marrow. Lineage-specific patterns of cytokine transcripts predate infection and suggest evolutionary selection for invariant but distinct types of effector responses among the earliest responding lymphocytes.

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Overexpression of CD1d by Keratinocytes in Psoriasis and CD1d-Dependent IFN-γ Production by NK-T Cells

The Journal of Immunology ◽

10.4049/jimmunol.165.7.4076 ◽

2000 ◽

Vol 165 (7) ◽

pp. 4076-4085 ◽

Cited By ~ 159

Author(s):

Brian Bonish ◽

Denis Jullien ◽

Yves Dutronc ◽

Barbara Bei Huang ◽

Robert Modlin ◽

...

Keyword(s):

T Cells ◽

Nk T Cells ◽

Ifn Γ

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SERPINB10 Contributes to Asthma by Inhibiting the Apoptosis of Allergenic Th2 Cells

10.21203/rs.3.rs-135747/v1 ◽

2020 ◽

Author(s):

Yuqing Mo ◽

Ling Ye ◽

Hui Cai ◽

Guiping Zhu ◽

Jian Wang ◽

...

Keyword(s):

T Cells ◽

Allergic Asthma ◽

Cd4 T Cells ◽

Quantitative Polymerase Chain Reaction ◽

Allergic Inflammation ◽

Specific Ige ◽

Th2 Cells ◽

Th1 Cells ◽

Th2 Response ◽

Th1 And Th2

Abstract Background: Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 1 (Th1) /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 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 contributes to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

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Peritoneal Fluid from Patients with Ovarian Endometriosis Displays Immunosuppressive Potential and Stimulates Th2 Response

International Journal of Molecular Sciences ◽

10.3390/ijms22158134 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8134

Author(s):

Joanna Olkowska-Truchanowicz ◽

Agata Białoszewska ◽

Aneta Zwierzchowska ◽

Alicja Sztokfisz-Ignasiak ◽

Izabela Janiuk ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Cytotoxic Activity ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Peritoneal Fluid ◽

Th17 Cells ◽

Th2 Response ◽

Immunoregulatory Cytokines ◽

Ifn Γ

Endometriosis is a common gynaecological disorder characterized by the ectopic growth of endometrial tissue outside the uterine cavity. It is associated with chronic pelvic inflammation and autoimmune reactivity manifesting by autoantibody production and abrogated cellular immune responses. Endometriotic peritoneal fluid contains various infiltrating leucocyte populations and a bulk of proinflammatory and immunoregulatory cytokines. However, the nature and significance of the peritoneal milieu in women with endometriosis still remains obscure. Therefore, the aim of the present study was to investigate the immunoregulatory activity of the peritoneal fluid (PF) from women with endometriosis. The peritoneal fluid samples were collected during laparoscopic surgery from 30 women with and without endometriosis. Immunoregulatory cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF) and chemokines (CCL2, CCL5, CXCL8 and CXCL9) were evaluated in PF and culture supernatants generated by unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells cultured in the presence of PF. The effect of PF on the generation of Treg and Th17 cells in CD4+ T cell cultures, as well as the natural cytotoxic activity of peripheral blood mononuclear cells, was also investigated. Concentrations of IL-6, IL-10, CCL2, CXCL8 and CXCL9 were significantly upregulated in the PF from women with endometriosis when compared to control women, whereas concentrations of other cytokines and chemokines were unaffected. The culturing of unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells in the presence of endometriotic PF resulted in the downregulation of their IL-2, IFN-γ, IL-17A and TNF production as compared to culture medium alone. On the other side, endometriotic PF significantly stimulated the production of IL-4 and IL-10. Endometriotic PF also stimulated the release of CCL2 and CXCL8, whereas the production of CCL5 and CXCL9 was downregulated. Endometriotic PF stimulated the generation of Treg cells and had an inhibitory effect on the generation of Th17 cells in cultures of CD4+ T cells. It also inhibited the NK cell cytotoxic activity of the peripheral blood lymphocytes. These results strongly imply that the PF from patients with endometriosis has immunoregulatory/immunosuppressive activity and shifts the Th1/Th2 cytokine balance toward the Th2 response, which may account for deviation of local and systemic immune responses. However, a similar trend, albeit not a statistically significant one, was also observed in case of PF from women without endometriosis, thus suggesting that peritoneal milieu may in general display some immunoregulatory/immunosuppressive properties. It should be stressed, however, that our present observations were made on a relatively small number of PF samples and further studies are needed to reveal possible mechanism(s) responsible for this phenomenon.

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Gamma Interferon Production by Hepatic NK T Cells during Escherichia coli Infection Is Resistant to the Inhibitory Effects of Oxidative Stress

Infection and Immunity ◽

10.1128/iai.71.5.2468-2477.2003 ◽

2003 ◽

Vol 71 (5) ◽

pp. 2468-2477 ◽

Cited By ~ 5

Author(s):

Guochi Zhang ◽

Robert Dru Nichols ◽

Masaru Taniguchi ◽

Toshinori Nakayama ◽

Michael J. Parmely

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Escherichia Coli ◽

T Cells ◽

Nk Cells ◽

Inhibitory Effects ◽

Gram Negative ◽

E Coli ◽

Nk T Cells ◽

Ifn Γ

ABSTRACT The reductive-oxidative status of tissues regulates the expression of many inflammatory genes that are induced during gram-negative bacterial infections. The cytokine gamma interferon (IFN-γ) is a potent stimulus for host inflammatory gene expression, and oxidative stress has been shown to inhibit its production in mice challenged with Escherichia coli bacteria. The objective of the present study was to characterize the cells that produced IFN-γ in a mouse bacterial peritonitis model and determine the effects of oxidative stress on their activation. The liver contained large numbers of IFN-γ-expressing lymphocytes following challenge with viable E. coli bacteria. The surface phenotypes of IFN-γ-expressing hepatic lymphocytes were those of natural killer (NK) cells (NK1.1+ CD3−), conventional T cells (NK1.1− CD3+), and NK T cells (NK1.1+ CD3+). Treating mice with diethyl maleate to deplete tissue thiols significantly impaired IFN-γ production by NK cells, conventional T cells, and CD1d-restricted NK T cells in response to E. coli challenge. However, IFN-γ expression by a subset of NK T cells, which did not bind α-galactosylceramide-CD1d tetramers, was resistant to the inhibitory effects of tissue oxidative stress. Stress-resistant IFN-γ-expressing cells were also predominantly CD8+ and bore γδ T-cell antigen receptors. The residual IFN-γ response by NK T cells may explain previous reports of hepatic gene expression following gram-negative bacterial challenge in thiol-depleted mice. The finding also demonstrates that innate immune cells differ significantly in their responses to altered tissue redox status.

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