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 Isolevuglandin-Modified Cardiac Proteins Drive CD4+ T Cell Activation in the Heart and Promote Cardiac Dysfunction

Circulation ◽  
2021 ◽  
Author(s):  
Njabulo Ngwenyama ◽  
Annet Kirabo ◽  
Mark Aronovitz ◽  
Francisco Velázquez ◽  
Francisco Carrillo-Salinas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cardiac Dysfunction ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Myocardial Oxidative Stress

Background: Despite the well-established association between T cell-mediated inflammation and non-ischemic heart failure (HF), the specific mechanisms triggering T cell activation during the progression of HF and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)-modified proteins that function as cardiac neoantigens to elicit CD4+ T cell receptor (TCR) activation and promote HF. Methods: We used transverse aortic constriction (TAC) in mice to trigger myocardial oxidative stress and T cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77 GFP reporter mice, which transiently express GFP upon TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation-deficient MhcII -/- mice, and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG-protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species (ROS) and IsoLGs in eliciting T cell immune responses in vivo by treating mice with the antioxidant TEMPOL, and the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) during TAC, and ex-vivo in mechanistic studies of CD4+ T cell proliferation in response to IsoLG-modified cardiac proteins. Results: We discovered that TCR antigen recognition increases in the left ventricle (LV) as cardiac dysfunction progresses, and identified a limited repertoire of activated CD4+ T cell clonotypes in the LV. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction since MhcII -/- mice reconstituted with CD4+ T cells, and OTII mice immunized with their cognate antigen were protected from TAC-induced cardiac dysfunction despite the presence of LV-infiltrated CD4+ T cells. Scavenging IsoLGs with 2-HOBA reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in ROS dependent dendritic cell accumulation of IsoLG-protein adducts which induced robust CD4+ T cell proliferation. Conclusions: Collectively, our study demonstrates an important role of ROS-induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T cell activation within the heart.

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 HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India

2019 ◽  
Vol 16 (4) ◽  
pp. 302-314
Author(s):  
Chinnambedu Ravichandran Swathirajan ◽  
Ramachandran Vignesh ◽  
Greer Waldrop ◽  
Uma Shanmugasundaram ◽  
Pannerselvam Nandagopal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Activation Rates ◽  
Hiv 1

Background:Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective:This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods:HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results:Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion:LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

scholarly journals Role of T-cell activation in salt-sensitive hypertension

2019 ◽  
Vol 316 (6) ◽  
pp. H1345-H1353 ◽  
Author(s):  
Jiafa Ren ◽  
Steven D. Crowley
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
T Subsets ◽  
Underlying Mechanisms ◽  
Salt Sensitive Hypertension

The contributions of T lymphocytes to the pathogenesis of salt-sensitive hypertension has been well established. Under hypertensive stimuli, naive T cells develop into different subsets, including Th1, Th2, Th17, Treg, and cytotoxic CD8+ T cells, depending on the surrounding microenviroment in organs. Distinct subsets of T cells may play totally different roles in tissue damage and hypertension. The underlying mechanisms by which hypertensive stimuli activate naive T cells involve many events and different organs, such as neoantigen presentation by dendritic cells, high salt concentration, and the milieu of oxidative stress in the kidney and vasculature. Infiltrating and activated T subsets in injured organs, in turn, exert considerable impacts on tissue dysfunction, including sodium retention in the kidney, vascular stiffness, and remodeling in the vasculature. Therefore, a thorough knowledge of T-cell actions in hypertension may provide novel insights into the development of new therapeutic strategies for patients with hypertension.

scholarly journals Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

2020 ◽  
Vol 21 (17) ◽  
pp. 6118 ◽  
Author(s):  
Marianna Szczypka
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Splice Variants ◽  
Cell Activity ◽  
Cell Functions ◽  
Simultaneous Inhibition ◽  
And Function

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

scholarly journals TRAIL suppresses gut inflammation and inhibits colitogeic T-cell activation in experimental colitis via an apoptosis-independent pathway

2019 ◽  
Vol 12 (4) ◽  
pp. 980-989 ◽  
Author(s):  
I. T. Chyuan ◽  
H. F. Tsai ◽  
C. S. Wu ◽  
P. N. Hsu
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Bowel Disease ◽  
Cell Activation ◽  
Gut Inflammation ◽  
Inflammatory Bowel ◽  
Colitis Model

AbstractTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals. Recently, accumulating evidence demonstrated that TRAIL regulates autoimmune inflammation and immune cell homeostasis in several autoimmune animal models, suggesting a novel immunoregulatory role of TRAIL in autoimmune diseases. However, the impact of TRAIL in inflammatory bowel disease is yet undefined. This study is to address the therapeutic effects and immunoregulatory role of TRAIL in autoimmune gut inflammation. We demonstrated herein that TRAIL significantly suppressed gut inflammation and reduced the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis model. Suppression of gut inflammation was not due to induction of apoptosis in colonic T cells, dendritic cells, or epithelium cells by TRAIL. In contrast, TRAIL directly inhibited activation of colitogenic T cells and development of gut inflammation in an adoptive transfer-induced colitis model. The anti-inflammatory effects of TRAIL on colitis were abolished when T cells from TRAIL receptor (TRAIL-R) knockout mice were adoptively transferred, suggesting that TRAIL regulates autoreactive colitogenic T-cell activation in the development of gut inflammation. Our results demonstrate that TRAIL effectively inhibited colonic T-cell activation and suppressed autoimmune colitis, suggesting a potential therapeutic application of TRAIL in human inflammatory bowel disease.

Potentiation of CD3-induced expression of the linker for activation of T cells (LAT) by the calcineurin inhibitors cyclosporin A and FK506

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2733-2741 ◽  
Author(s):  
David Peters ◽  
Masahiro Tsuchida ◽  
Eric R. Manthei ◽  
Tausif Alam ◽  
Clifford S. Cho ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cyclosporin A ◽  
T Cell Activation ◽  
Messenger Rna ◽  
Cell Activation ◽  
Calcineurin Inhibitors ◽  
Northern Blotting ◽  
Cellular Level ◽  
Therapeutic Implications

The activation of blood cells, including T cells, triggers intracellular signals that control the expression of critical molecules, including cytokines and cytokine receptors. We show that T-cell receptor (TCR) ligation increases the cellular level of the protein linker for activation of T cells (LAT), a molecule critical for T-cell development and function. T-cell activation increased LAT messenger RNA, as determined by reverse transcription–polymerase chain reaction and by Northern blotting. The TCR-induced increase in LAT expression involved the activation of the serine/threonine kinases PKC and MEK, because inhibitors of these kinases blocked the increase in LAT. Accordingly, the PKC activator phorbol myristate acetate up-regulated LAT expression. Strikingly, the calcineurin inhibitors cyclosporin A (CsA) and FK506 strongly potentiated TCR-induced LAT expression, suggesting that the activation of calcineurin following TCR ligation negatively regulates LAT expression. Accordingly, Ca++ ionophores, which can activate calcineurin by increasing intracellular Ca++, blocked the TCR-induced increase in cellular LAT. CsA and FK506 blocked the Ca++ionophores' inhibitory effect on LAT expression. Notably, CsA and FK506 preferentially up-regulated TCR-induced LAT expression; under the same conditions, these compounds did not increase the expression of 14 other molecules that previously had been implicated in T-cell activation. These data show that TCR-induced LAT expression involves the activation of the PKC-Erk pathway and is negatively regulated by the activation of calcineurin. Furthermore, the potentiation of TCR-induced LAT expression by CsA and FK506 suggests that the action of these agents involves up-regulating the cellular level of critical signaling molecules. These findings may have important therapeutic implications.

scholarly journals Akt Fine-tunes NF-κB-dependent Gene Expression during T Cell Activation

2011 ◽  
Vol 286 (41) ◽  
pp. 36076-36085 ◽  
Author(s):  
Jing Cheng ◽  
Binh Phong ◽  
David C. Wilson ◽  
Raphael Hirsch ◽  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gene Profiling ◽  
Leukocyte Activation ◽  
Mrna Transcription ◽  
Tnf Α ◽  
Fine Tune

Activation of the NF-κB signaling pathway is critical for leukocyte activation and development. Although previous studies suggested a role for the Akt kinase in coupling the T cell antigen receptor and CD28 to NF-κB activation in T cells, the nature of the role of Akt in this pathway is still unclear. Using a targeted gene profiling approach, we found that a subset of NF-κB-dependent genes required Akt for optimal up-regulation during T cell activation. The selective effects of Akt were manifest at the level of mRNA transcription and p65/RelA binding to upstream promoters and appear to be due to altered formation of the Carma1-Bcl10 complex. The proinflammatory cytokine TNF-α was found to be particularly sensitive to Akt inhibition or knockdown, including in primary human blood T cells and a murine model of rheumatoid arthritis. Our findings are consistent with a hierarchy in the expression of NF-κB-dependent genes, controlled by the strength and/or duration of NF-κB signaling. More broadly, our results suggest that defining the more graded effects of signaling, such as those demonstrated here for Akt and the NF-κB pathway, is important to understanding how cells can fine-tune signaling responses for optimal sensitivity and specificity.

scholarly journals T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia

2019 ◽  
Vol 17 (10) ◽  
pp. 1042-1052 ◽  
Author(s):  
Simo Xia ◽  
Xiang Liu ◽  
Xuetao Cao ◽  
Sheng Xu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Aplastic Anemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Autoreactive T Cell

Abstract The role of Bruton’s tyrosine kinase (BTK) in BCR signaling is well defined, and BTK is involved in B-cell development, differentiation, and malignancies. However, the expression of Btk in T cells and its role in T-cell function remain largely unknown. Here, we unexpectedly found high expression and activation of BTK in T cells. Deficiencies in BTK resulted in the impaired activation and proliferation of autoreactive T cells and ameliorated bone marrow failure (BMF) in aplastic anemia. Mechanistically, BTK is activated after TCR engagement and then phosphorylates PLCγ1, thus promoting T-cell activation. Treatment with acalabrutinib, a selective BTK inhibitor, decreased T-cell proliferation and ameliorated BMF in mice with aplastic anemia. Our results demonstrate an unexpected role of BTK in optimal T-cell activation and in the pathogenesis of autoimmune aplastic anemia, providing insights into the molecular regulation of T-cell activation and the pathogenesis of T-cell-mediated autoimmune disease.

CD11b+gr-1+ myeloid Derived Suppressor Cells (MDSC) In Normal Bone Marrow Suppress T Cell Proliferation and Enhance T-Regulatory Function Via a IL10-, IL4- and IDO-Independent Mechanism

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4801-4801 ◽  
Author(s):  
Parvin Forghani ◽  
Wayne Harris ◽  
jian-Ming Li ◽  
M.R. Khorramizadeh ◽  
Edmund Waller
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Regulatory Function ◽  
T Cell Proliferation ◽  
Suppressive Activity ◽  
Ifn Γ

Abstract Abstract 4801 MDSC have been described as an important negative regulators of autologous anti-cancer immune responses. Considering the important role of MDSC in immune regulation in allogenic stem cell and organ transplantation, we undertook an investigation of the mechanism(s) by which MDSC inhibit T–cell activation and proliferation, and tested the hypothesis that local cytokine secretion or IDO activity is required for suppression of T-cell proliferation. Two separate populations CD11bhiGr-1hi and CD11bhi Gr-1int were isolated by high-speed FACS from lineage- BM antigen presenting cells (C57 & BALB/c mice). Both MDSC subsets had potent capacity for in–vitro suppression of CD4+ and CD8+ T cells proliferation in response to anti-CD3/anti-CD28 beads and Con A. A ratio of 0.5/1 MDSC: T-cells were sufficient to inhibit >66% control levels of T-cell proliferation. MDSC isolated from transgenic mice that had been “knocked-out” for IFN-γ and IDO had equivalent suppressive activity as MDSC from wild-type donors. Addition of saturating concentrations of anti IL-10 and IL-4 MAb, or in combination with anti- IFN-γ MAb did not abrogate MDSC-suppressive activity. Ex-vivo culture of MDSC with mitogen-activated T-cells generated two—fold more Fox-p3 T-reg compared with cultures of T cell plus mitogen. Data will be presented regarding the novel role of MDSC involving in the homeostasis regulation of normal T-cell activation and proliferation in non-tumor-bearing mice. Disclosures: No relevant conflicts of interest to declare.

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