scholarly journals Mechanisms of Cytokine-Induced Glioma Immunosuppression

2010 ◽  
Vol 3 (1) ◽  
pp. 30-35 ◽  
Author(s):  
Alexander Ksendzovsky ◽  
Roberta P. Glick ◽  
Paul Polak ◽  
Maria-Vittoria Simonini ◽  
Anothony J. Sharp ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Differentiation ◽  
Tumor Vaccine ◽  
Glioma Cells ◽  
T Cell Differentiation ◽  
Conditioned Media ◽  
Activated T Cells ◽  
Proliferation And Differentiation ◽  
Tumor Survival

Glioma immunosuppression includes the secretion of cytokines that down-regulate the host immune response resulting in tumor survival. The mechanisms of cytokine-induced immunosuppression are not well understood and are considered in this study. Glioma cells were incubated with supernatant from activated and naïve T-cells. A separate culture of T-cells (naïve, CD3-activated, and CD3/CD28 activated) was then incubated with conditioned media from the treated glioma cells as well as individual and combination recombinant cytokines. These T-cells were tested for viability, proliferation and IFN-􀀁 release. Several conclusions were drawn from these experiments: cytotoxicity is not a means of glioma immunosuppression, glioma conditioned media decreases proliferation of CD3/CD28 activated T-cells acting potentially through IL10 and IGFBP, and these cytokines also decrease IFN-􀀁 secretion from all varieties of T-cells suggesting that T-cell differentiation away from TH1 is another potential means of immunosuppression. These results necessitate further analysis of proliferation and differentiation as potential mechanisms of immunosuppression and the incorporation of this knowledge into the production of a more efficacious tumor vaccine.

scholarly journals MiR-374b-5p Regulates T Cell Differentiation and Is Associated with rEg.P29 Immunity

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Dongjie Li ◽  
Xiancai Du ◽  
Mingxing Zhu ◽  
Songhao Yang ◽  
Wei Zhao
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
T Cells ◽  
Cell Differentiation ◽  
Echinococcus Granulosus ◽  
Secondary Infection ◽  
T Cell Differentiation ◽  
Mrna Levels ◽  
Th17 Differentiation ◽  
Th1 Immune Response

Cystic echinococcosis (CE) is a zoonotic disease caused by Echinococcus granulosus (Eg) infection. Our previous study confirmed that recombinant Eg.P29 (rEg.P29) could protect against echinococcus granulosus secondary infection in sheep and mice. The aim of the study was to investigate the association between immunoprotection of rEg.P29 vaccine and mmu-miR-374b-5p (miR-374b-5p) and study the immunity influence of miR-374b-5p on CD4+ T cells in mice spleen. MiR-374b-5p level was significantly increased after the second-week and the fourth week of vaccination with rEg.P29. Overexpression of miR-374b-5p increased IFN-γ, IL-2, IL-17A mRNA levels and decreased IL-10 mRNA levels in CD4+ T cells. Moreover, the inhibition of miR-374b-5p decreased IFN-γ and IL-17A and increased IL-10 mRNA levels in CD4+ T cells; this was further confirmed by the flow cytometry. The vaccination of rEg.P29 enhanced miR-374b-5p expression that was associated with a higher Th1 and Th17 immune response, a lower IL-10 mRNA production with miR-374b-5p overexpression, a lower Th1 immune response, and a higher IL-10 mRNA levels with miR-374b-5p inhibitions. To sum up, these data suggest that miR-374b-5p may participate in rEg.P29 immunity by regulating Th1 and Th17 differentiation.

scholarly journals The Calcineurin-NFAT Axis Controls Allograft Immunity in Myeloid-Derived Suppressor Cells through Reprogramming T Cell Differentiation

2014 ◽  
Vol 35 (3) ◽  
pp. 598-609 ◽  
Author(s):  
Xiao Wang ◽  
Yujing Bi ◽  
Lixiang Xue ◽  
Jiongbo Liao ◽  
Xi Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Suppressor Cells ◽  
T Cell Differentiation ◽  
Interleukin 4 ◽  
Myeloid Derived Suppressor Cells ◽  
Activated T Cells ◽  
Immunological Mechanisms ◽  
Signaling Axis

While cyclosporine (CsA) inhibits calcineurin and is highly effective in prolonging rejection for transplantation patients, the immunological mechanisms remain unknown. Herein, the role of calcineurin signaling was investigated in a mouse allogeneic skin transplantation model. The calcineurin inhibitor CsA significantly ameliorated allograft rejection. In CsA-treated allograft recipient mice, CD11b+Gr1+myeloid-derived suppressor cells (MDSCs) were functional suppressive immune modulators that resulted in fewer gamma interferon (IFN-γ)-producing CD8+T cells and CD4+T cells (TH1 T helper cells) and more interleukin 4 (IL-4)-producing CD4+T cells (TH2) and prolonged allogeneic skin graft survival. Importantly, the expression of NFATc1 is significantly diminished in the CsA-induced MDSCs. Blocking NFAT (nuclear factor of activated T cells) with VIVIT phenocopied the CsA effects in MDSCs and increased the suppressive activities and recruitment of CD11b+Gr1+MDSCs in allograft recipient mice. Mechanistically, CsA treatment enhanced the expression of indoleamine 2,3-dioxygenase (IDO) and the suppressive activities of MDSCs in allograft recipients. Inhibition of IDO nearly completely recovered the increased MDSC suppressive activities and the effects on T cell differentiation. The results of this study indicate that MDSCs are an essential component in controlling allograft survival following CsA or VIVIT treatment, validating the calcineurin-NFAT-IDO signaling axis as a potential therapeutic target in transplantation.

scholarly journals Akt-Fas to Quell Aberrant T Cell Differentiation and Apoptosis in Covid-19

2020 ◽  
Vol 11 ◽  
Author(s):  
Anthony J. Leonardi ◽  
Rui B. Proenca
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Function ◽  
T Cell Differentiation ◽  
Serine Threonine Kinase ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
T Cell Lymphopenia ◽  
Infected Cells

Aberrant T cell differentiation and lymphopenia are hallmarks of severe COVID-19 disease. Since T cells must race to cull infected cells, they are quick to differentiate and achieve cytotoxic function. With this responsiveness, comes hastened apoptosis, due to a coupled mechanism of death and differentiation in both CD4+ and CD8+ lymphocytes via CD95 (Fas) and serine-threonine kinase (Akt). T cell lymphopenia in severe cases may represent cell death or peripheral migration. These facets depict SARS-Cov-2 as a lympho-manipulative pathogen; it distorts T cell function, numbers, and death, and creates a dysfunctional immune response. Whether preservation of T cells, prevention of their aberrant differentiation, and expansion of their population may alter disease course is unknown. Its investigation requires experimental interrogation of the linked differentiation and death pathway by agents known to uncouple T cell proliferation and differentiation in both CD4+ and CD8+ T cells.

scholarly journals Akt Fas to Quell Aberrant T Cell Differentiation and Death in Covid-19

2020 ◽  
Author(s):  
Anthony Joseph Leonardi
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Function ◽  
T Cell Differentiation ◽  
Serine Threonine Kinase ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Hastened Death ◽  
Infected Cells

Aberrant T cell differentiation and lymphopenia are hallmarks of severe COVID-19 disease. Since T cells must race to cull infected cells, they are quick to differentiate and achieve cytotoxic function. With this responsiveness, unfortunately, comes hastened death, due to a coupled mechanism of death and differentiation in both CD4+ and CD8+ lymphocytes via CD95 (Fas) and serine-threonine kinase (Akt). T cell lymphopenia in severe cases may represent cell death or peripheral migration. These facets depict SARS-Cov-2 as a lympho-manipulative pathogen; it distorts T cell function, numbers, and death, and creates a dysfunctional immune response. Whether preservation of T cells, prevention of their differentiation, and expansion of their population may alter disease course is unknown. Its investigation requires experimental interrogation of the linked differentiation and death pathway by agents known to uncouple T cell proliferation and differentiation in both CD4+ and CD8+ T cells.

scholarly journals Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease

2021 ◽  
pp. annrheumdis-2020-219335
Author(s):  
Emma Garcia-Melchor ◽  
Giacomo Cafaro ◽  
Lucy MacDonald ◽  
Lindsay A N Crowe ◽  
Shatakshi Sood ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
T Cell Activation ◽  
Cell Activation ◽  
Conditioned Media ◽  
Tissue Remodelling ◽  
Activated T Cells ◽  
T Cell Migration

ObjectivesIncreasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation.MethodsT cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes.ResultsSignificant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte–T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio.ConclusionsInteraction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders.

158 Inhibition of PI3Kδ improves tumor specific T cell immunity and metabolic fitness

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A172-A172
Author(s):  
Guillermo Rangel Rivera ◽  
Guillermo Rangel RIvera ◽  
Connor Dwyer ◽  
Dimitrios Arhontoulis ◽  
Hannah Knochelmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Immunity ◽  
Mitochondrial Function ◽  
T Cell Differentiation ◽  
Tumor Control ◽  
T Cell Therapy

BackgroundDurable responses have been observed with adoptive T cell therapy (ACT) in some patients. However, current protocols used to expand T cells often exhibit suboptimal tumor control. Failure in these therapies has been attributed to premature differentiation and impaired metabolism of the infused T cells. Previous work done in our lab showed that reduced PI3Kδ signaling improved ACT. Because PI3Kγ and PI3Kδ have critical regulatory roles in T cell differentiation and function, we tested whether inhibiting PI3Kγ could recapitulate or synergize PI3Kδ blockade.MethodsTo test this, we primed melanoma specific CD8+ pmel-1 T cells, which are specific to the glycoprotein 100 epitope, in the presence of PI3Kγ (IPI-459), PI3Kδ (CAL101 or TGR-1202) or PI3Kγ/δ (IPI-145) inhibitors following antigen stimulation with hgp100, and then infused them into 5Gy total body irradiated B16F10 tumor bearing mice. We characterized the phenotype of the transferred product by flow cytometry and then assessed their tumor control by measuring the tumor area every other day with clippers. For metabolic assays we utilized the 2-NBDG glucose uptake dye and the real time energy flux analysis by seahorse.ResultsSole inhibition of PI3Kδ or PI3Kγ in vitro promoted greater tumor immunity and survival compared to dual inhibition. To understand how PI3Kδ or PI3Kγ blockade improved T cell therapy, we assessed their phenotype. CAL101 treatment produced more CD62LhiCD44lo T cells compared to IPI-459, while TGR-1202 enriched mostly CD62LhiCD44hi T cells. Because decreased T cell differentiation is associated with mitochondrial metabolism, we focused on CAL101 treated T cells to study their metabolism. We found that CAL101 decreased glucose uptake and increased mitochondrial respiration in vitro, indicating augmented mitochondrial function.ConclusionsThese findings indicate that blocking PI3Kδ is sufficient to mediate lasting tumor immunity of adoptively transferred T cells by preventing premature differentiation and improving mitochondrial fitness. Our data suggest that addition of CAL101 to ACT expansion protocols could greatly improve T cell therapies for solid tumors by preventing T cell differentiation and improving mitochondrial function.

scholarly journals Potential Antiinflammatory Role of Insulin via the Preferential Polarization of Effector T Cells toward a T Helper 2 Phenotype

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 346-353 ◽  
Author(s):  
Alexander Viardot ◽  
Shane T. Grey ◽  
Fabienne Mackay ◽  
Donald Chisholm
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Insulin Receptor ◽  
T Cell Differentiation ◽  
Receptor Expression ◽  
T Helper ◽  
Type Response ◽  
Helper Type

Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, because antiinflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood. The insulin receptor is expressed on resting neutrophils, monocytes, and B cells, but is not detectable on T cells. However, significant up-regulation of insulin receptor expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper type 2 (Th2)-type response, decreasing the T helper type 1 to Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, with the interferon-γ to IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin. Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its antiinflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.

Expression of a proto-oncogene (proto-myb) in hemopoietic tissues of mice

1984 ◽  
Vol 4 (7) ◽  
pp. 1206-1212
Author(s):  
D Sheiness ◽  
M Gardinier
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Lymph Nodes ◽  
Blot Hybridization ◽  
Protein Product ◽  
T Cell Differentiation ◽  
Dot Blot ◽  
Cellular Homolog ◽  
Old Mice ◽  
Transforming Gene

This study addressed the possibility that proto-myb (also called c-myb), the cellular homolog of a retroviral transforming gene, plays a role in hemopoiesis, particularly during maturation of T cells. By gel blot hybridization, we confirmed previous reports that proto-myb transcripts are found at much higher levels in thymic lymphocytes and cells of the erythroid lineage than in other tissue sources. Using dot blot hybridizations, we demonstrated further that similar levels of proto-myb expression are found in thymic lymphocytes taken from young mice with active thymuses and from old mice whose thymuses have undergone involution and that the extent of proto-myb expression decreases at least 10-fold as T cells progress from immature cortical thymocytes to the mature, resting T cells taken from lymph nodes. These results suggest that the protein product of proto-myb functions during T-cell differentiation.

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