Blockade of Costimulation Prevents Infection-Induced Immunopathology in Interleukin-10-Deficient Mice

ABSTRACT Interleukin-10 (IL-10) is associated with inhibition of cell-mediated immunity and downregulation of the expression of costimulatory molecules required for T-cell activation. When IL-10-deficient (IL-10KO) mice are infected with Toxoplasma gondii, they succumb to a T-cell-mediated shock-like reaction characterized by the overproduction of IL-12 and gamma interferon (IFN-γ) associated with widespread necrosis of the liver. Since costimulation is critical for T-cell activation, we investigated the role of the CD28-B7 and CD40-CD40 ligand (CD40L) interactions in this infection-induced immunopathology. Our studies show that infection of mice with T. gondii resulted in increased expression of B7 and CD40 that was similar in wild-type and IL-10KO mice. In vivo blockade of the CD28-B7 or CD40-CD40L interactions following infection of IL-10KO mice with T. gondii did not affect serum levels of IFN-γ or IL-12, nor did it prevent death in these mice. However, when both pathways were blocked, the IL-10KO mice survived the acute phase of infection and had reduced serum levels of IFN-γ and alanine transaminase as well as decreased expression of inducible nitric oxide synthase in the liver and spleen. Analysis of parasite-specific recall responses from infected IL-10KO mice revealed that blockade of the CD40-CD40L interaction had minimal effects on cytokine production, whereas blockade of the CD28-B7 interaction resulted in decreased production of IFN-γ but not IL-12. Further reduction of IFN-γ production was observed when both costimulatory pathways were blocked. Together, these results demonstrate that the CD28-B7 and CD40-CD40L interactions are involved in the development of infection-induced immunopathology in the absence of IL-10.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.278.6.l1221 ◽

2000 ◽

Vol 278 (6) ◽

pp. L1221-L1230 ◽

Cited By ~ 35

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.

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Early Immune Markers Associated withMycobacterium aviumsubsp.paratuberculosisInfection in a Neonatal Calf Model

Clinical and Vaccine Immunology ◽

10.1128/cvi.00359-10 ◽

2011 ◽

Vol 18 (3) ◽

pp. 393-405 ◽

Cited By ~ 35

Author(s):

J. R. Stabel ◽

S. Robbe-Austerman

Keyword(s):

T Cell ◽

T Cell Activation ◽

Lymphocyte Proliferation ◽

Cell Activation ◽

The Other ◽

T Cell Subsets ◽

Cell Mediated Immunity ◽

Activation Markers ◽

Oral Inoculation ◽

Ifn Γ

ABSTRACTThe objective of this study was to observe early markers of cell-mediated immunity in naïve calves infected withMycobacterium aviumsubsp.paratuberculosisand how expression of these markers evolved over the 12-month period of infection. Groups for experimental infection included control (noninfected), oral (infected orally withM. aviumsubsp.paratuberculosisstrain K-10), oral/DXM (pretreatment with dexamethasone before oral inoculation), intraperitoneal (i.p.) inoculation, and oral/M (oral inoculation with mucosal scrapings from a cow with clinical disease) groups. One of the earliest markers to emerge was antigen-specific gamma interferon (IFN-γ). Only i.p. inoculated calves had detectable antigen-specific IFN-γ responses at 7 days, with responses of the other infection groups becoming detectable at 90 and 120 days. All infection groups maintained robust IFN-γ responses for the remainder of the study. At 1 month, calves in the oral and oral/M groups had higher antigen-stimulated interleukin-10 (IL-10) levels than calves in the other treatment groups, but IL-10 secretion declined by 12 months for all calves. T-cell activation markers such as CD25, CD26, CD45RO, and CD5 were significantly upregulated in infected calves compared to noninfected controls. Oral inoculation of calves resulted in significantly increased antigen-specific lymphocyte proliferation at 9 and 12 months, as well as inducible nitric oxide synthase (iNOS) secretion at 6 and 12 months. These results demonstrate that infection of naïve calves withM. aviumsubsp.paratuberculosisinvoked early immunologic responses characterized by robust antigen-specific IFN-γ responses and induction of CD25 and CD45RO expression on T-cell subsets. These were followed by antigen-specific lymphocyte proliferation, iNOS secretion, and expression of CD26 and CD5brightmarkers in the latter part of the 12-month study.

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Humulus scandens Exhibits Immunosuppressive Effects in Vitro and in Vivo by Suppressing CD4+ T Cell Activation

The American Journal of Chinese Medicine ◽

10.1142/s0192415x1450058x ◽

2014 ◽

Vol 42 (04) ◽

pp. 921-934 ◽

Cited By ~ 2

Author(s):

Jinjin Feng ◽

Yingchun Wu ◽

Yang Yang ◽

Weiqi Jiang ◽

Shaoping Hu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Interferon Γ ◽

Delayed Type Hypersensitivity ◽

Ifn Γ ◽

Humulus Scandens

Humulus scandens, rich in flavonoids, is a traditional Chinese medicine. It is widely used in China to treat tuberculosis, dysentery and chronic colitis. In this study, the major active faction of Humulus scandens (H.S) was prepared. Then, its immunosuppressive effects and underlying mechanisms on T cell activation were investigated in vitro and in vivo. Results showed that H.S significantly inhibited the proliferation of splenocytes induced by concanavalin A, lipopolysaccharides, and mixed-lymphocyte reaction in vitro. Additionally, H.S could dramatically suppress the proliferation and interferon-γ (IFN-γ) production from T cells stimulated by anti-CD3 and anti-CD28. Flow cytometric results confirmed that H.S could suppress the differentiation of IFN-γ-producing type 1 helper T cells (Th1). Furthermore, using ovalbumin immunization-induced T cell reaction and CD4+ T-cell-mediated delayed type hypersensitivity reaction, H.S the immunosuppressive effects of H.S was also demonstrated in vivo. Western blot results showed that H.S could impede the activation of both Erk1/2 and P38 in primary T cells triggered by anti-CD3/28. Collectively, the active fraction of H.S showed promising immunosuppressive activities both in vitro and in vivo.

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Sphingosine kinase inhibition exerts both pro- and anti-atherogenic effects in low-density lipoprotein receptor-deficient (LDL-R−/−) mice

Thrombosis and Haemostasis ◽

10.1160/th11-08-0583 ◽

2012 ◽

Vol 107 (03) ◽

pp. 552-561 ◽

Cited By ~ 16

Author(s):

Francesco Potì ◽

Martine Bot ◽

Sara Costa ◽

Valeria Bergonzini ◽

Lynn Maines ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Atherosclerotic Lesion ◽

Density Lipoprotein ◽

Sphingosine Kinase ◽

Cell Number ◽

Ifn Γ

SummarySphingosine 1-phosphate (S1P), a lysosphingolipid associated with high-density lipoprotein (HDL), contributes to the anti-atherogenic potential attributed to this lipoprotein. This study examined whether a reduction of S1P plasma levels affects atherosclerosis in a murine model of disease. LDL-R−/−mice on Western diet were given ABC294640, an inhibitor of sphingosine kinase (SphK) for 16 weeks. ABC294640 decreased plasma S1P by approximately 30%. However, ABC294640 failed to affect atherosclerotic lesion formation. Plasma triglycerides were reduced whereas total and HDL-cholesterol remained unchanged in course of ABC294640 treatment. ABC294640 increased plasma interleukin (IL)-12p70 and RANTES concentration as well as IL-12p70, RANTES and interferon (IFN)-γ production by peritoneal cells and this was paralleled by enhanced activity of peritoneal and spleen dendritic cells as evidenced by up-regulation of CD86 and MHC-II on CD11c+ cells. As a consequence, increased T-cell activation was noted in ABC294640-treated mice as indicated by enhanced CD4+ splenocyte proliferation, IFN-γ and IL-2 production, and CD69 expression. Con-comitantly, however, ABC294640 treatment redistributed CD4+ and CD8+ cells from blood to lymphatic organs and reduced T-cell number within atherosclerotic lesions. In addition, plasma sVCAM-1, sICAM-1, and MCP-1 levels as well as in vivo leukocyte adhesion and CCL19-induced T-cell penetration into peritoneum were lower in ABC294640-treated animals. In vitro experiments demonstrated reduced VCAM-1 and ICAM-1 expression and lymphocyte adhesion to endothelial cells exposed to ABC294640. In conclusion, treatment with SphK inhibitor leads to both pro- and anti-atherogenic effects in LDL-R−/− mice. As a consequence, SphK inhibition fails to affect atherosclerosis despite significant S1P reduction in plasma.

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Activation of OX40 and CD27 Costimulatory Signalling in Sheep through Recombinant Ovine Ligands

Vaccines ◽

10.3390/vaccines8020333 ◽

2020 ◽

Vol 8 (2) ◽

pp. 333

Author(s):

José Manuel Rojas ◽

Alí Alejo ◽

Jose Miguel Avia ◽

Daniel Rodríguez-Martín ◽

Carolina Sánchez ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

T Cell Proliferation ◽

Tnf Superfamily ◽

Infected Cells ◽

Ifn Γ ◽

Necrosis Factor

Members of the tumour necrosis factor (TNF) superfamily OX40L and CD70 and their receptors are costimulating signalling axes critical for adequate T cell activation in humans and mice but characterisation of these molecules in other species including ruminants is lacking. Here we cloned and expressed the predicted ovine orthologues of the receptors OX40 and CD27, as well as soluble recombinant forms of their potential ovine ligands, OaOX40L and OaCD70. Using biochemical and immunofluorescence analyses, we show that both signalling axes are functional in sheep. We show that oligomeric recombinant ligand constructs are able to induce signalling through their receptors on transfected cells. Recombinant defective human adenoviruses were constructed to express the soluble forms of OaOX40L and OaCD70. Both proteins were detected in the supernatant of adenovirus-infected cells and shown to activate NF-κB signalling pathway through their cognate receptor. These adenovirus-secreted OaOX40L and OaCD70 forms could also activate ovine T cell proliferation and enhance IFN-γ production in CD4+ and CD8+ T cells. Altogether, this study provides the first characterisation of the ovine costimulatory OX40L-OX40 and CD70-CD27 signalling axes, and indicates that their activation in vivo may be useful to enhance vaccination-induced immune responses in sheep and other ruminants.

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Proliferative Responses of Harbor Seal (Phoca vitulina) T Lymphocytes to Model Marine Pollutants

Developmental Immunology ◽

10.1080/10446670310001593523 ◽

2002 ◽

Vol 9 (4) ◽

pp. 215-221 ◽

Cited By ~ 20

Author(s):

Jennifer C. C. Neale ◽

Judith A. Van de Water ◽

James T. Harvey ◽

Ronald S. Tjeerdema ◽

M. Eric Gershwin

Keyword(s):

T Cell ◽

T Cell Activation ◽

Marine Mammals ◽

Cell Activation ◽

Cell Function ◽

Harbor Seal ◽

Cell Mediated Immunity ◽

Population Declines

In recent years, population declines related to viral outbreaks in marine mammals have been associated with polluted coastal waters and high tissue concentrations of certain persistent, lipophilic contaminants. Such observations suggest a contributing role of contaminant-induced suppression of cell-mediated immunity leading to decreased host resistance. Here, we assessed the effects of the prototypic polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (B[a]P), and two polychlorinated biphenyls (PCBs), CB-156 and CB-80, on the T-cell proliferative response to mitogen in harbor seal peripheral lymphocytes. Despite the variability associated with our samples from free-ranging harbor seals, we observed a clear suppressive effect of B[a]P (10 uM) exposure on T cell mitogenesis. Exposures to 10 uM CB-156 and CB-80, and 1.0 and 0.1 uM B[a]P, did not produce significant depression in lymphoproliferation. Exposure to the model PAH at 10 uM resulted in a 61% (range 34-97%) average reduction in lymphoproliferation. We were able to rule out a direct cytotoxic effect of B[a]P, indicating that observed effects were due to altered T cell function. Based on ourin vitroresults, we hypothesize that extensive accumulation of PAH by top-trophic-level marine mammals could alter T cell activationin vivoand impaired cell-mediated immunity against viral pathogens.

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Contribution of Interleukin-12 (IL-12) and the CD28/B7 and CD40/CD40 Ligand Pathways to the Development of a Pathological T-Cell Response in IL-10-Deficient Mice

Infection and Immunity ◽

10.1128/iai.70.12.6940-6947.2002 ◽

2002 ◽

Vol 70 (12) ◽

pp. 6940-6947 ◽

Cited By ~ 12

Author(s):

Ulrike Wille ◽

Eric N. Villegas ◽

Linden Craig ◽

Robert Peach ◽

Christopher A. Hunter

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Response ◽

Cd40 Ligand ◽

T Cell Response ◽

Interleukin 12 ◽

Cell Mediated Immunity ◽

Cell Functions ◽

Ifn Γ

ABSTRACT The ability of interleukin-10 (IL-10) to suppress accessory cell functions required for optimal T-cell activation makes it an important inhibitor of cell-mediated immunity. Thus, after infection with the protozoan parasite Toxoplasma gondii, IL-10 knockout (KO) mice develop a CD4+-T-cell-dependent shock-like reaction with high levels of IL-12 and gamma interferon (IFN-γ) in serum, leading to death of mice during the acute phase of infection. Previous studies from this laboratory have shown that simultaneous blockade of CD28 and CD40 can prevent this lethal reaction by inhibiting the production of IFN-γ. However, the blockade of costimulation did not affect systemic levels of IL-12. To better understand the relationship between IL-12 and the CD28 and CD40 pathways in mediating immune hyperactivity, antagonists of these factors were used to determine their effects on the development of a pathological T-cell response in IL-10 KO mice. Blockade of IL-12 or the CD28/B7 interaction alone did not affect survival; however, the combined blockade of both pathways resulted in decreased production of IFN-γ and the survival of IL-10 KO mice. To assess the role of the two ligands for CD28, B7.1 and B7.2, IL-10 KO mice were treated with αIL-12 plus αB7.1 or αB7.2 or the combination of all three antibodies. These studies revealed that blockade of both B7 molecules is required for decreased production of IFN-γ and survival of infected IL-10 KO mice, suggesting that B7.1 and B7.2 can contribute to the lethal shock-like reaction in IL-10 KO mice. In contrast, neutralization of IL-12 and blockade of the CD40/CD40 ligand (CD40L) interaction in vivo did not alter the production of IFN-γ and only resulted in a small delay in time to death of mice. Together, these data suggest that the CD28/B7 interaction has a central role in the development of a pathological T-cell response in IL-10 KO mice, which is distinct from the role of the CD40/CD40L and IL-12 pathways.

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IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

Yearbook of Endocrinology ◽

10.1016/s0084-3741(08)79083-8 ◽

2008 ◽

Vol 2008 ◽

pp. 233-235

Author(s):

B.L. Clarke

Keyword(s):

T Cell ◽

Bone Loss ◽

T Cell Activation ◽

Cell Activation ◽

Osteoclast Formation ◽

Ifn Γ

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A Novel Kinase Inhibitor AX-0085 Inhibits Interferon-γ-Mediated Induction of PD-L1 Expression and Promotes Immune Reaction to Lung Adenocarcinoma Cells

Cells ◽

10.3390/cells11010019 ◽

2021 ◽

Vol 11 (1) ◽

pp. 19

Author(s):

Jusong Kim ◽

Haeyeon Jang ◽

Gyu Jin Lee ◽

Yelim Hur ◽

Juhee Keum ◽

...

Keyword(s):

T Cell ◽

Lung Adenocarcinoma ◽

T Cell Activation ◽

Cell Activation ◽

Kinase Inhibitor ◽

Interferon Γ ◽

Adenocarcinoma Cells ◽

Ifn Γ

In this study, we describe a novel kinase inhibitor AX-0085 which can suppress the induction of PD-L1 expression by Interferon-γ (IFN-γ) in lung adenocarcinoma (LUAD) cells. AX-0085 effectively blocks JAK2/STAT1 signaling initiated by IFN-γ treatment and prevents nuclear localization of STAT1. Importantly, we demonstrate that AX-0085 reverses the IFN-γ-mediated repression of T cell activation in vitro and enhances the anti-tumor activity of anti-PD-1 antibody in vivo when used in combination. Finally, transcriptomic analyses indicated that AX-0085 is highly specific in targeting the IFN-γ-pathway, thereby raising the possibility of applying this reagent in combination therapy with checkpoint inhibitor antibodies. It may be particularly relevant in cases in which PD-L1-mediated T cell exhaustion leads to immunoevasive phenotypes.

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