Novel Regulation of CD80/CD86-induced Phosphatidylinositol 3-Kinase Signaling by NOTCH1 Protein in Interleukin-6 and Indoleamine 2,3-Dioxygenase Production by Dendritic Cells

Koorella, Chandana; Nair, Jayakumar; Murray, Megan; Carlson, Louise; Watkins, Stephanie K.; Lee, Kelvin P.

doi:10.1074/jbc.m113.519686

Cited by 71 publications

(64 citation statements)

References 50 publications

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“…Unlike previous studies, our data did not reveal induction of IL-6 or indoleamine 2,3-dioxygenase (IDO) in abatacept-treated CD11c1 cells (35,36). Thus, it appears that abatacept treatment during priming has an inhibitory effect on the function of CD11c1 APCs.…”

Section: Effect Of Abatacept On T Cells and Apcs During Primary Immuncontrasting

confidence: 98%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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Objective. To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.Methods. We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c1 APCs. These were combined with detailed immunologic and full genome transcriptional analyses.Results. We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells.Conclusion. This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.

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Section: Effect Of Abatacept On T Cells and Apcs During Primary Immuncontrasting

confidence: 98%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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“…Our findings provide direct evidence for a CTLA-4-mediated activation of Akt that promotes DC FoxO1 nuclear exclusion. In line with our data, Koorella et al demonstrated that binding to CD80/CD86 activates the PI3K/ Akt pathway in human DCs (39). Subsequently, activated Akt phosphorylates FoxO3 and drives its exit from the nucleus, abrogating the FoxO3 repressive role in IL-6 expression.…”

Section: -Immunized Rag1supporting

confidence: 77%

“…This is consistent with a recent report showing that crosslinking of CD80/CD86 in human DCs results in activation of the PI3K/Akt pathway (39). Of interest, in the same study, ligation of CD28-Ig markedly induced p85 phosphorylation (38), whereas our results demonstrate that the autophagy pathway was not affected upon treatment of BMDCs with CD28-Ig.…”

Section: -Immunized Rag1supporting

confidence: 71%

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Tregs restrain dendritic cell autophagy to ameliorate autoimmunity

Alissafi¹,

Banos²,

Boon³

et al. 2017

Journal of Clinical Investigation

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“…As well as its role in normal cell growth, regulation of blood glucose homeostasis and lipid metabolism (10)(11)(12)(13)(14), the PI3K-AKT-mTOR pathway plays an important role in regulating the immune system and cytokines production by immune cells (15). Emerging data indicate that the inhibition of PI3K signaling reduces the generation and suppresses the secretion of proinflammatory cytokines and leads to an attenuated immune response (15)(16)(17)(18). It is known that mTOR inhibitors regulate the immune function and are licensed for use in renal transplantation (19,20).…”

Section: Introductionmentioning

confidence: 99%

Higher Risk of Infections with PI3K–AKT–mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials

Rafii

Roda

Geuna

et al. 2015

Clinical Cancer Research

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Novel antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogs. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2 or multi-kinase inhibitors is unknown. Methods In this retrospective case-control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K-AKT-mTOR pathway inhibitors (cases) vs a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K-AKT-mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K-AKT-mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapies. Results The incidence of all grade infection was significantly higher with all single agent PI3K-AKT-mTOR inhibitors compared to the control group (27% vs 8% respectively, OR: 4.26, 95% CI: 1.9-9.1, p=0.0001). The incidence of grade 3 and 4 infection was also significantly higher with PI3K-AKT-mTOR inhibitors compared to the control group (10.3% vs 3%, OR: 3.74, 95% CI: 1.1-12.4, p=0.02). Also the combination of PI3K-AKT-mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR: 4.79, 95% CI: 2.0-11.2, p=0.0001) and high grade (OR: 2.87, 95% CI: 1.0-7.6, p=0.03) infection when compared with single agent PI3K-AKT-mTOR inhibitors. Conclusion Inhibitors of the PI3K-AKT-mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K-AKT-mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents.

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Novel Regulation of CD80/CD86-induced Phosphatidylinositol 3-Kinase Signaling by NOTCH1 Protein in Interleukin-6 and Indoleamine 2,3-Dioxygenase Production by Dendritic Cells

Cited by 71 publications

References 50 publications

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Tregs restrain dendritic cell autophagy to ameliorate autoimmunity

Higher Risk of Infections with PI3K–AKT–mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials

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