scholarly journals 648 T cell intrinsic caspase 1 signaling negatively regulates T cell anti-tumor response

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A677-A677
Author(s):  
Young Kim ◽  
Michael Korrer ◽  
Cara Lang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Myeloid Cell ◽  
Tumor Burden ◽  
Negative Regulator ◽  
Cell Vaccine ◽  
Null Mouse ◽  
Caspase 1

BackgroundThe inflammasome is a multi-protein signaling pathway in immune and epithelial cells that is important for activation of the innate immune system and protection from pathogens. This pathway is well characterized in myeloid cell populations, however the T cell intrinsic effects of the inflammasome are not well understood.MethodsIn this study we utilize an inflammasome null mouse model to investigate the functional and phenotypic differences in inflammasome null and wildtype T cells. We utilize a whole cell vaccine against B16 mouse tumors to generate B16 tumor antigen specific T cells. In addition, we utilize clinically relevant PD-1 inhibitory antibodies to model checkpoint inhibition with inflammasome null T cells.ResultsHere we show that the inflammasome is expressed and activated in tumor infiltrating T cells in both humans and mice. We find that inflammasome null T cells have an altered phenotype causing them to become more proliferative and increase killing capacity. In addition, caspase 1 null T cells are present in the TME at a greater frequency than wildtype T cells. We also show that caspase 1 knockout T cells have higher checkpoint expression, most notably an increase in PD-1 expression, and combination caspase 1 and PD-1 blockade results in a significant reduction in tumor burden.ConclusionsTherefore, we propose that T cell intrinsic inflammasome signaling acts as a negative regulator to inhibit T cell activation and cytotoxicity. Together our findings reveal the inflammasome as an attractive pathway that can be targeted in combination with checkpoint blockade therapies to improve anti-tumor T cell responses.

Abstract 219: Deficiency of the T Cell Regulator Cbl-B Aggravates Atherosclerosis by Inducing CD8 + T Cell-Mediated Macrophage Death

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Tom T Seijkens ◽  
Holger Winkels ◽  
Marion Gijbels ◽  
Jan A Kuivenhoven ◽  
Ljubica Perisic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Aortic Arch ◽  
T Cell Activation ◽  
Cell Activation ◽  
B Cell Lymphoma ◽  
Negative Regulator ◽  
Atherosclerotic Plaques ◽  
Chow Diet ◽  
Plaque Area

Aims: The E3-ligase CBL-B ( Casitas B-cell Lymphoma-B ) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but their regulation in this disease remains largely unknown; thus, we studied the function of CBL-B in atherogenesis. Methods and Results: Here we investigated the effect of CBL-B deficiency in hyperlipidemic Apoe -/- mice in atherosclerosis. At the age of 20 weeks, chow diet-fed Cbl-b -/- Apoe -/- mice showed a significant increase in plaque area in the aortic arch, due to greater macrophage infiltration. Cbl-b -/- Apoe -/- macrophages displayed strong recruitment towards MCP1 and showed an increase in oxidized (ox)LDL uptake. In the aortic root of the same Cbl-b -/- Apoe -/- mice, where more advanced plaques were present than in the aortic arch, plaque area rose by 40%, accompanied by a dramatic change in plaque phenotype. Plaques contained fewer macrophages, had larger necrotic cores, and harboured more CD8 + T cells. The CD8 + T cells of Cbl-b -/- Apoe -/- mice were less susceptible to apoptosis and less resistant to Treg suppression. The increase in CD8 + T cells in the plaque effected greater macrophage apoptosis, resulting in enhanced necrotic core formation. Moreover, CBL-B gene expression was downregulated in human atherosclerotic plaques, and positively correlated with FoxP3 expression, indicating an atheroprotective effect. Conclusion: CBL-B is an important regulator of innate and adaptive immune reactions in atherosclerosis, by mediating macrophage recruitment and activation, CD8 + T cell activation, and CD8 + T cell-induced macrophage death in atherosclerotic plaques.

scholarly journals The RING ubiquitin E3 RNF114 interacts with A20 and modulates NF-κB activity and T-cell activation

2014 ◽  
Vol 5 (8) ◽  
pp. e1399-e1399 ◽  
Author(s):  
M S Rodriguez ◽  
I Egaña ◽  
F Lopitz-Otsoa ◽  
F Aillet ◽  
M P Lopez-Mato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Zinc Finger Protein ◽  
Inflammatory Diseases ◽  
Negative Regulator ◽  
Cell Mediated Immune Response ◽  
Cycle Regulation ◽  
Hybrid Screening

Abstract Accurate regulation of nuclear factor-κB (NF-κB) activity is crucial to prevent a variety of disorders including immune and inflammatory diseases. Active NF-κB promotes IκBα and A20 expression, important negative regulatory molecules that control the NF-κB response. In this study, using two-hybrid screening we identify the RING-type zinc-finger protein 114 (RNF114) as an A20-interacting factor. RNF114 interacts with A20 in T cells and modulates A20 ubiquitylation. RNF114 acts as negative regulator of NF-κB-dependent transcription, not only by stabilizing the A20 protein but also IκBα. Importantly, we demonstrate that in T cells, the effect of RNF114 is linked to the modulation of T-cell activation and apoptosis but is independent of cell cycle regulation. Altogether, our data indicate that RNF114 is a new partner of A2O involved in the regulation of NF-κB activity that contributes to the control of signaling pathways modulating T cell-mediated immune response.

scholarly journals ROG Negatively Regulates T-Cell Activation but Is Dispensable for Th-Cell Differentiation

2005 ◽  
Vol 25 (2) ◽  
pp. 554-562 ◽  
Author(s):  
Bok Yun Kang ◽  
Shi-Chuen Miaw ◽  
I-Cheng Ho
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Target Gene ◽  
Interleukin 2 ◽  
Negative Regulator ◽  
Th2 Cells ◽  
Th Cells ◽  
And Function

ABSTRACT ROG, a transcriptional repressor, is a direct target gene of NF-AT and a putative negative regulator of T-cell activation. In addition, overexpression of ROG suppresses the activity of GATA-3, implying a role of ROG in the differentiation and function of Th cells. Despite these observations, the function of ROG has yet to be confirmed by loss-of-function approaches. Here we report that ROG-deficient T cells are hypersensitive to anti-CD3 stimulation and produce more interleukin-2 (IL-2) due to enhanced NF-κB activity. ROG-deficient dendritic cells also produce more IL-12p40, another NF-κB target gene. However, ROG-deficient Th cells are capable of differentiating into Th1 and Th2 cells, and ROG-deficient mice have no defect in mounting appropriate Th immune responses in vivo. Thus, ROG is dispensable for the differentiation and function of Th cells but serves as a mediator of NF-AT-initiated suppression of NF-κB. Its mechanism of action and its expression pattern are distinct from those of other transcription factors negatively regulating the activation of T cells.

scholarly journals PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt

2018 ◽  
Vol 215 (12) ◽  
pp. 3165-3179 ◽  
Author(s):  
Uzodinma U. Uche ◽  
Ann R. Piccirillo ◽  
Shunsuke Kataoka ◽  
Stephanie J. Grebinoski ◽  
Louise M. D’Cruz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Modulation ◽  
Cell Activation ◽  
Sh2 Domain ◽  
Cellular Growth ◽  
Negative Regulator ◽  
Regulatory Subunit ◽  
Kringle Domain

Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kringle and p85-like domains are necessary for TrIP inhibition of PI3K and that TrIP is down-modulated from the surface of T cells during T cell activation. In addition, we present evidence that the kringle domain may modulate TrIP function by mediating oligomerization. Using an inducible knockout mouse model, we show that TrIP-deficient T cells exhibit more robust activation and can mediate clearance of Listeria monocytogenes infection faster than WT mice. Thus, TrIP is a negative regulator of T cell activation and may represent a novel target for immune modulation.

scholarly journals Tumor Growth Enhances Cross-Presentation Leading to Limited T Cell Activation without Tolerance

2002 ◽  
Vol 195 (4) ◽  
pp. 423-435 ◽  
Author(s):  
Linh T. Nguyen ◽  
Alisha R. Elford ◽  
Kiichi Murakami ◽  
Kristine M. Garza ◽  
Stephen P. Schoenberger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Burden ◽  
High Avidity ◽  
Cross Presentation ◽  
Advanced Tumor

Using a tumor model of spontaneously arising insulinomas expressing a defined tumor-associated antigen, we investigated whether tumor growth promotes cross-presentation and tolerance of tumor-specific T cells. We found that an advanced tumor burden enhanced cross-presentation of tumor-associated antigens to high avidity tumor-specific T cells, inducing T cell proliferation and limited effector function in vivo. However, contrary to other models, tumor-specific T cells were not tolerized despite a high tumor burden. In fact, in tumor-bearing mice, persistence and responsiveness of adoptively transferred tumor-specific T cells were enhanced. Accordingly, a potent T cell–mediated antitumor response could be elicited by intravenous administration of tumor-derived peptide and agonistic anti-CD40 antibody or viral immunization and reimmunization. Thus, in this model, tumor growth promotes activation of high avidity tumor-specific T cells instead of tolerance. Therefore, the host remains responsive to T cell immunotherapy.

scholarly journals CD6 as a potential target for treating multiple sclerosis

2017 ◽  
Vol 114 (10) ◽  
pp. 2687-2692 ◽  
Author(s):  
Yan Li ◽  
Nora G. Singer ◽  
Joy Whitbred ◽  
Michael A. Bowen ◽  
David A. Fox ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Negative Regulator ◽  
Microvascular Endothelial Cell ◽  
Cell Responses ◽  
T Cell Survival

CD6 was established as a marker of T cells more than three decades ago, and recent studies have identified CD6 as a risk gene for multiple sclerosis (MS), a disease in which autoreactive T cells are integrally involved. Nevertheless, the precise role of CD6 in regulating T-cell responses is controversial and its significance in the pathogenesis of various diseases remains elusive, partly due to the lack of animals engineered to alter expression of the CD6 gene. In this report, we found that CD6 KO mice showed decreased pathogenic T-cell responses, reduced spinal cord T-cell infiltration, and attenuated disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CD6-deficient T cells exhibited augmented activation, but also significantly reduced survival and proliferation after activation, leading to overall decreased Th1 and Th17 polarization. Activated CD6-deficient T cells also showed impaired infiltration through brain microvascular endothelial cell monolayers. Furthermore, by developing CD6 humanized mice, we identified a mouse anti-human CD6 monoclonal antibody that is highly effective in treating established EAE without depleting T cells. These results suggest that (i) CD6 is a negative regulator of T-cell activation, (ii) at the same time, CD6 is a positive regulator of activated T-cell survival/proliferation and infiltration; and (iii) CD6 is a potential new target for treating MS and potentially other T-cell–driven autoimmune conditions.

scholarly journals Yap suppresses T cell function and infiltration in the tumor microenvironment

2019 ◽  
Author(s):  
Eleni Stampouloglou ◽  
Anthony Federico ◽  
Emily Slaby ◽  
Stefano Monti ◽  
Gregory L. Szeto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Biology ◽  
Cell Activation ◽  
Cell Function ◽  
T Cell Responses ◽  
Negative Regulator ◽  
Cell Responses

ABSTRACTA major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon activation of CD4+ and CD8+ T cells and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap in T cells results in enhanced T cell activation, differentiation and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T cell responses in the tumor microenvironment and as a key negative regulator of T cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T cell biology, and suggest that inhibiting Yap activity improves T cell responses in cancer.

scholarly journals Releasing the Brake: Targeting Cbl-b to Enhance Lymphocyte Effector Functions

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Stephanie Wallner ◽  
Thomas Gruber ◽  
Gottfried Baier ◽  
Dominik Wolf
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Malignant Tumors ◽  
Current Knowledge ◽  
Negative Regulator ◽  
Therapeutic Concept ◽  
Therapeutic Implications

The E3 ubiquitin ligase Cbl-b is an established nonredundant negative regulator of T-cell activation. Cbl-b fine-tunes the activation threshold of T cells and uncouples T cells from their vital need of a costimulatory signal to mount a productive immune response. Accordingly, mice deficient incblbare prone to autoimmunity and reject tumors. The latter has been described to be mediatedviaCD8+T cells, which are hyperactive and more abundant in shrinking tumors ofcblb-deficient animals. This might at least also in part be mediated by resistance ofcblb-deficient T cells to negative cues exerted by tumor-associated immuno-suppressive factors, such as TGF-βand regulatory T cells (Treg). Experiments usingcblb-deficient T cells either alone or in combination with vaccines validate the therapeutic concept of enhancing the efficacy of adoptively transferred lymphocytes to treat malignant tumors. This paper summarizes the current knowledge about the negative regulatory role of Cbl-b in T-cell activation and its potential therapeutic implications for cancer immunotherapy.

scholarly journals Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist

2020 ◽  
Vol 8 (1) ◽  
pp. e000493 ◽  
Author(s):  
Karin M Knudson ◽  
Kristin C Hicks ◽  
Yohei Ozawa ◽  
Jeffrey Schlom ◽  
Sofia R Gameiro
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Tumor Burden ◽  
Receptor Expression ◽  
Antitumor Efficacy ◽  
Cytokine Signaling ◽  
Immune Correlates

BackgroundAnti(α)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies to reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte trafficking to the tumor microenvironment (TME) may improve efficacy. N-809 is a first-in-class bifunctional agent comprising the interleukin (IL)-15 superagonist N-803 fused to two αPD-L1 domains. Thus, N-809 can potentially stimulate effector immune cells through IL-15 and block immunosuppressive PD-L1. Here, we examined the antitumor efficacy and immunomodulatory effects of N-809 versus N-803+αPD-L1 combination.MethodsThe ability of N-809 to block PD-L1 and induce IL-15-dependent immune effects was examined in vitro and in vivo. Antitumor efficacy of N-809 or N-803+αPD-L1 was evaluated in two murine carcinoma models and an extensive analysis of immune correlates was performed in the tumor and tumor-draining lymph node (dLN).ResultsWe demonstrate that N-809 blocks PD-L1 and induces IL-15-dependent immune effects. N-809 was well-tolerated and reduced 4T1 lung metastasis, decreased MC38 tumor burden and increased survival versus N-803+αPD-L1. Compared with N-803+αPD-L1, N-809 enhanced natural killer (NK) and CD8+T-cell activation and function in the dLN and TME, relating to increased gene expression associated with interferon and cytokine signaling, lymphoid compartment, costimulation and cytotoxicity. The higher number of TME CD8+T cells was attributed to enhanced infiltration, not in situ expansion. Increased TME NK and CD8+T-cell numbers correlated with augmented chemokine ligands and receptors. Moreover, in contrast to N-803+αPD-L1, N-809 reduced immunosuppressive regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (M-MDSC) and M2-like macrophages in the TME.ConclusionsOur results suggest that N-809 functions by a novel immune mechanism to promote antitumor efficacy. Foremost, N-809 enhances intratumoral lymphocyte numbers by increasing trafficking via altered chemokine levels in the TME and chemokine receptor expression on CD8+T cells and NK cells. In addition, N-809 reduces immunosuppressive and pro-tumorigenic immune cells in the TME, including Treg, M2-like macrophages and M-MDSC. Overall, these novel effects of N-809 promote an inflamed TME, leading to lower tumor burden and increased survival. These results provide mechanistic insight and rationale supporting the potential clinical study of N-809 in patients with carcinoma.

scholarly journals ZAP-70 Regulates Autoimmune Arthritis via Alterations in T Cell Activation and Apoptosis

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 504 ◽  
Author(s):  
Réka Kugyelka ◽  
Lilla Prenek ◽  
Katalin Olasz ◽  
Zoltán Kohl ◽  
Bálint Botz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Severe Disease ◽  
Negative Regulator ◽  
Human Rheumatoid Arthritis ◽  
Autoantibody Production

T cells play an essential role in the pathogenesis of both human rheumatoid arthritis (RA) and its murine models. A key molecule in T cell activation is ZAP-70, therefore we aimed to investigate the effects of partial ZAP-70 deficiency on the pathogenesis of recombinant human G1(rhG1)-induced arthritis (GIA), a well-established mouse model of RA. Arthritis was induced in BALB/c and ZAP-70+/− heterozygous mice. Disease progression was monitored using a scoring system and in vivo imaging, antigen-specific proliferation, cytokine and autoantibody production was measured and T cell apoptotic pathways were analyzed. ZAP-70+/− mice developed a less severe arthritis, as shown by both clinical picture and in vitro parameters (decreased T cell proliferation, cytokine and autoantibody production). The amount of cleaved Caspase-3 increased in arthritic ZAP-70+/− T cells, with no significant changes in cleaved Caspase-8 and -9 levels; although expression of Bim, Bcl-2 and Cytochrome C showed alterations. Tyrosine phosphorylation was less pronounced in arthritic ZAP-70+/− T cells and the amount of Cbl-b—a negative regulator of T cell activation—decreased as well. We hypothesize that the less severe disease seen in the partial absence of ZAP-70 might be caused by the decreased T cell activation accompanied by increased apoptosis.

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