Marek’s Disease Virus Modulates T Cell Proliferation via Activation of Cyclooxygenase 2-Dependent Prostaglandin E2

Marek’s disease virus (MDV), an avian alphaherpesvirus, infects chickens, transforms CD4+ T cells, and induces immunosuppression early during infection. However, the exact mechanisms involved in MDV-induced immunosuppression are yet to be identified. Here, our results demonstrate that MDV infection in vitro and in vivo induces activation of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). This exerts its inhibitory effects on T cell proliferation at day 21 post infection via PGE2 receptor 2 (EP2) and receptor 4 (EP4). Impairment of the MDV-induced T cell proliferation was associated with downregulation of IL-2 and transferrin uptake in a COX-2/PGE2 dependent manner in vitro. Interestingly, oral administration of a COX-2 inhibitor, meloxicam, during MDV infection inhibited COX-2 activation and rescued T cell proliferation at day 21 post infection. Taken together, our results reveal a novel mechanism that contributes to immunosuppression in the MDV-infected chickens.

Download Full-text

Prostaglandin E2 enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells

Blood ◽

10.1182/blood-2008-05-157123 ◽

2009 ◽

Vol 113 (11) ◽

pp. 2451-2460 ◽

Cited By ~ 67

Author(s):

Petra Krause ◽

Markus Bruckner ◽

Christina Uermösi ◽

Eva Singer ◽

Marcus Groettrup ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Prostaglandin E2 ◽

Cell Interaction ◽

Costimulatory Molecules ◽

Critical Parameters ◽

T Cell Proliferation ◽

Maturation Stimulus

Abstract Dendritic cell (DC)–based immunotherapy of malignant diseases relies on 2 critical parameters: antigen transport from the periphery to draining lymph nodes and efficient priming of primary and stimulation of secondary immune responses. Prostaglandin E2 (PGE2) signaling has been shown to be pivotal for DC migration toward lymph node–derived chemokines in vitro and in vivo. Here, we demonstrate that PGE2 induced the expression of the costimulatory molecules OX40L, CD70, and 4-1BBL on human DCs. Short triggering by PGE2 early during DC maturation was sufficient to induce the costimulatory molecules. The expression of the costimulatory molecules was independent of the maturation stimulus but strictly dependent on PGE2 on both monocyte-derived (Mo) DCs and peripheral blood myeloid (PB) DCs. PGE2-matured MoDCs showed enhanced costimulatory capacities resulting in augmented antigen-specific CD4+ and CD8+ T-cell proliferation in primary and recall T-cell responses. Blocking OX40/OX40L signaling impaired the enhanced T-cell proliferation induced by PGE2-matured MoDCs. Moreover, MoDCs matured in the presence of PGE2 induced the expression of OX40, OX40L, and CD70 on T cells facilitating T-cell/T-cell interaction that warrant long-lasting costimulation. This newly identified parameter will help to further optimize DC-based immunotherapy.

Download Full-text

Prostaglandin E2Induction Suppresses the Th1 Immune Responses in Cattle with Johne's Disease

Infection and Immunity ◽

10.1128/iai.00910-17 ◽

2018 ◽

Vol 86 (5) ◽

pp. e00910-17 ◽

Cited By ~ 8

Author(s):

Yamato Sajiki ◽

Satoru Konnai ◽

Tomohiro Okagawa ◽

Asami Nishimori ◽

Naoya Maekawa ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Cytokine Production ◽

Johne's Disease ◽

Johne’S Disease ◽

T Cell Proliferation ◽

Content Type ◽

Th1 Cytokine ◽

Cox 2

ABSTRACTJohne's disease, caused byMycobacterium aviumsubsp.paratuberculosis, is a bovine chronic infection that is endemic in Japan and many other countries. The expression of immunoinhibitory molecules is upregulated in cattle with Johne's disease, but the mechanism of immunosuppression is poorly understood. Prostaglandin E2(PGE2) is immunosuppressive in humans, but few veterinary data are available. In this study, functional and kinetic analyses of PGE2were performed to investigate the immunosuppressive effect of PGE2during Johne's disease.In vitroPGE2treatment decreased T-cell proliferation and Th1 cytokine production and upregulated the expression of immunoinhibitory molecules such as interleukin-10 and programmed death ligand 1 (PD-L1) in peripheral blood mononuclear cells (PBMCs) from healthy cattle. PGE2was upregulated in sera and intestinal lesions of cattle with Johne's disease.In vitrostimulation with Johnin purified protein derivative (J-PPD) induced cyclooxygenase-2 (COX-2) transcription, PGE2production, and upregulation of PD-L1 and immunoinhibitory receptors in PBMCs from cattle infected withM. aviumsubsp.paratuberculosis. Therefore, Johnin-specific Th1 responses could be limited by the PGE2pathway in cattle. In contrast, downregulation of PGE2with a COX-2 inhibitor promoted J-PPD-stimulated CD8+T-cell proliferation and Th1 cytokine production in PBMCs from the experimentally infected cattle. PD-L1 blockade induced J-PPD-stimulated CD8+T-cell proliferation and interferon gamma productionin vitro. Combined treatment with a COX-2 inhibitor and anti-PD-L1 antibodies enhanced J-PPD-stimulated CD8+T-cell proliferationin vitro, suggesting that the blockade of both pathways is a potential therapeutic strategy to control Johne's disease. The effects of COX-2 inhibition warrant further study as a novel treatment of Johne's disease.

Download Full-text

Keratinocytes Regulate the Threshold of Inflammation by Inhibiting T Cell Effector Functions

Cells ◽

10.3390/cells10071606 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1606

Author(s):

Peter Seiringer ◽

Stefanie Eyerich ◽

Kilian Eyerich ◽

Daniela Dittlein ◽

Anna Caroline Pilz ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Cytokine Production ◽

Nickel Sulfate ◽

Human Keratinocytes ◽

T Cell Proliferation ◽

Effector Functions ◽

The Impact ◽

Cell Effector

Whilst the importance of keratinocytes as a first-line defense has been widely investigated, little is known about their interactions with non-resident immune cells. In this study, the impact of human keratinocytes on T cell effector functions was analyzed in an antigen-specific in vitro model of allergic contact dermatitis (ACD) to nickel sulfate. Keratinocytes partially inhibited T cell proliferation and cytokine production. This effect was dependent on the keratinocyte/T cell ratio and was partially reversible by increasing the number of autologous dendritic cells. The inhibition of T cell proliferation by keratinocytes was independent of the T cell subtype and antigen presentation by different professional antigen-presenting cells. Autologous and heterologous keratinocytes showed comparable effects, while the fixation of keratinocytes with paraformaldehyde abrogated the immunosuppressive effect. The separation of keratinocytes and T cells by a transwell chamber, as well as a cell-free keratinocyte supernatant, inhibited T cell effector functions to the same amount as directly co-cultured keratinocytes, thus proving that soluble factor/s account for the observed suppressive effects. In conclusion, keratinocytes critically control the threshold of inflammatory processes in the skin by inhibiting T cell proliferation and cytokine production.

Download Full-text

Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro

Frontiers in Immunology ◽

10.3389/fimmu.2020.592553 ◽

2020 ◽

Vol 11 ◽

Author(s):

Christian Binder ◽

Felix Sellberg ◽

Filip Cvetkovski ◽

Erik Berglund ◽

David Berglund

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mixed Lymphocyte Reaction ◽

T Cell Proliferation ◽

Allogeneic Mixed Lymphocyte Reaction ◽

Dependent Cell

Antibodies are commonly used in organ transplant induction therapy and to treat autoimmune disorders. The effects of some biologics on the human immune system remain incompletely characterized and a deeper understanding of their mechanisms of action may provide useful insights for their clinical application. The goal of this study was to contrast the mechanistic properties of siplizumab with Alemtuzumab and rabbit Anti-Thymocyte Globulin (rATG). Mechanistic assay systems investigating antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis and complement-dependent cytotoxicity were used to characterize siplizumab. Further, functional effects of siplizumab, Alemtuzumab, and rATG were investigated in allogeneic mixed lymphocyte reaction. Changes in T cell activation, T cell proliferation and frequency of naïve T cells, memory T cells and regulatory T cells induced by siplizumab, Alemtuzumab and rATG in allogeneic mixed lymphocyte reaction were assessed via flow cytometry. Siplizumab depleted T cells, decreased T cell activation, inhibited T cell proliferation and enriched naïve and bona fide regulatory T cells. Neither Alemtuzumab nor rATG induced the same combination of functional effects. The results presented in this study should be used for further in vitro and in vivo investigations that guide the clinical use of immune modulatory biologics.

Download Full-text

Prostaglandin E2 produced by inducible COX-2 and mPGES-1 promoting cancer cell proliferation in vitro and in vivo

Life Sciences ◽

10.1016/j.lfs.2014.07.042 ◽

2014 ◽

Vol 116 (1) ◽

pp. 43-50 ◽

Cited By ~ 37

Author(s):

Diana Ruan ◽

Shui-Ping So

Keyword(s):

Cell Proliferation ◽

Prostaglandin E2 ◽

Cancer Cell ◽

Cancer Cell Proliferation ◽

Cox 2 ◽

Proliferation In Vitro

Download Full-text

IL-10 mRNA Engineered MSCs Demonstrate Enhanced Anti-Inflammation in an Acute GvHD Model

Cells ◽

10.3390/cells10113101 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3101

Author(s):

Cuiping Zhang ◽

Mina Delawary ◽

Peng Huang ◽

Jennifer A. Korchak ◽

Koji Suda ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Therapeutic Potential ◽

Immune Dysregulation ◽

T Cell Proliferation ◽

Immunomodulatory Effects ◽

Freezing And Thawing ◽

Mrna Transfection ◽

Clinical Conditions

Mesenchymal stem cells (MSCs) are used in various studies to induce immunomodulatory effects in clinical conditions associated with immune dysregulation such as graft versus host disease (GvHD). However, most of these clinical trials failed to go beyond early phase 2 studies because of limited efficacy. Various methods have been assessed to increase the potency of MSCs. IL-10 is an anti-inflammatory cytokine that is known to modulate immune responses in GvHD. In this study, we evaluated the feasibility of transfecting IL-10 mRNA to enhance MSC therapeutic potential. IL-10 mRNA engineered MSCs (eMSCs-IL10) maintained high levels of IL-10 expression even after freezing and thawing. IL-10 mRNA transfection did not appear to alter MSC intrinsic characteristics. eMSCs-IL10 significantly suppressed T cell proliferation relative to naïve MSCs in vitro. In a mouse model for GvHD, eMSCs-IL10 induced a decrease in plasma level of potent pro-inflammatory cytokines and inhibited CD4+ and CD8+ T cell proliferation in the spleen. In summary, our studies demonstrate the feasibility of potentiating MSCs to enhance their immunomodulatory effects by IL-10 mRNA transfection. The use of non-viral transfection may generate a safe and potent MSC product for treatment of clinical conditions associated with immune dysregulation such as GvHD.

Download Full-text