scholarly journals Upregulation of Intracellular Glutathione by Fibroblast-Derived Factor(s): Enhanced Survival of Activated T Cells in the Presence of Low Bcl-2

Blood ◽  
1997 ◽  
Vol 89 (7) ◽  
pp. 2453-2460 ◽  
Author(s):  
Helena Hyde ◽  
Nicola J. Borthwick ◽  
George Janossy ◽  
Michael Salmon ◽  
Arne N. Akbar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Interleukin 2 ◽  
Buthionine Sulfoximine ◽  
Activated T Cells ◽  
Large Molecular Weight ◽  
Low Levels ◽  
T Cell Survival

Abstract Activated interleukin-2 (IL-2)–dependent T cells express high levels of Bcl-2 protein. On cytokine withdrawal, Bcl-2 expression decreases and the cells die rapidly by apoptosis. We have previously shown that the survival of IL-2–deprived T cells can be promoted by factor(s) secreted by fibroblasts. Here we report that reduced glutathione (GSH), but not its oxidized counterpart GSSG, also enhances the in vitro survival of these cells. Exogenous GSH mediates its effect intracellularly, as (1) endogenous glutathione concentrations are increased up to fivefold in the presence of GSH, and (2) acivicin, an inhibitor of transmembrane GSH transport, abrogates GSH-dependent survival. The GSH-rescued T cells do not proliferate and express only low levels of Bcl-2, resembling WI38 fibroblast-rescued T cells. We, therefore, investigated a role for GSH in fibroblast-promoted T-cell survival. We show that WI38-promoted survival results in elevated GSH levels in surviving T cells and is abrogated by buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. Furthermore, both WI38-promoted T-cell survival and GSH upregulation are associated with large molecular weight molecules (<30 kD). Thus, the upregulation of GSH by WI38 fibroblasts appears to be crucial in their ability to enhance the survival of cytokine-deprived activated T cells in vitro.

scholarly journals Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

2016 ◽  
Vol 90 (17) ◽  
pp. 7967-7979 ◽  
Author(s):  
Xavier Dagenais-Lussier ◽  
Mouna Aounallah ◽  
Vikram Mehraj ◽  
Mohamed El-Far ◽  
Cecile Tremblay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Cd4 T Cell ◽  
Tryptophan Catabolism ◽  
T Cell Survival ◽  
Memory Cd4 T Cells ◽  
Hiv 1

ABSTRACTEarly HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidantN-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection.IMPORTANCEThe persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.

scholarly journals Low Levels of NF-κB/p65 Mark Anergic CD4+T Cells and Correlate with Disease Severity in Sarcoidosis

2010 ◽  
Vol 18 (2) ◽  
pp. 223-234 ◽  
Author(s):  
Nam-Sihk Lee ◽  
Laura Barber ◽  
Ali Kanchwala ◽  
Carter J. H. Childs ◽  
Yash P. Kataria ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Protein Levels ◽  
T Cell Anergy ◽  
Ifn Γ ◽  
Low Levels ◽  
Stimulation Of

ABSTRACTT lymphocytes from patients with sarcoidosis respond weakly when stimulated with mitogen or antigen. However, the mechanisms responsible for this anergy are not fully understood. Here, we investigated the protein levels of nuclear transcription factor NF-κB (p50, p65, and p105), IκBα (inhibitor of NF-κB), T-cell receptor (TCR) CD3ζ-chain, tyrosine kinase p56LCK, and nuclear factor of activated T cells c2 (NF-ATc2) in peripheral blood CD4+T cells from patients with sarcoidosis. Baseline expression of p65 in these lymphocytes was reduced in 50% of patients. The reduced levels of p65 in sarcoid CD4+T cells concurred with decreased levels of p50, p105, CD3ζ, p56LCK, IκBα, and NF-ATc2. Polyclonal stimulation of NF-κB-deficient sarcoid T cells resulted in reduced expression of CD69 and CD154, decreased proliferation, and cytokine (i.e., interleukin 2 [IL-2] and gamma interferon [IFN-γ]) production. The clinical significance of these findings is suggested by the association between low p65 levels and the development of more severe and active sarcoidosis. Although correlative, our results support a model in which multiple intrinsic signaling defects contribute to peripheral T-cell anergy and the persistence of chronic inflammation in sarcoidosis.

scholarly journals Activation-Induced Inhibition of Interleukin 6–Mediated T Cell Survival and Signal Transducer and Activator of Transcription 1 Signaling

2000 ◽  
Vol 191 (6) ◽  
pp. 915-926 ◽  
Author(s):  
T. Kent Teague ◽  
Brian C. Schaefer ◽  
David Hildeman ◽  
Jeremy Bender ◽  
Tom Mitchell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Cascades ◽  
Signal Transducer ◽  
Activated T Cells ◽  
History Of ◽  
T Cell Survival ◽  
Determining Factor ◽  
Activation Status

The cytokines interleukin (IL)-2, IL-4, IL-6, IL-7, and IL-15 have all previously been shown to inhibit resting T cell death in vitro. We have found a difference in the response of T cells to IL-6, depending on the activation status of the cells. IL-6 inhibited the death of naive T cells, but had no effect on the death of either superantigen-activated T cells, or T cells bearing memory markers. This was true even when the resting and activated T cells were isolated from the same animal; thus, the determining factor for IL-6 insensitivity was the activation status or activation history of the cell, and not the milieu in the animal from which the cells were isolated. Activated T cells expressed lower levels of IL-6 receptors on their surfaces, yet there were sufficient levels of receptors for signaling, as we observed similar levels of signal transducer and activator of transcription (Stat)3 phosphorylation in resting and activated T cells treated with IL-6. However, there was profound inhibition of IL-6–induced Stat1 phosphorylation in activated T cells compared with resting T cells. These data suggest that there is activation-induced inhibition of IL-6 receptor signaling in T cells. This inhibition appears to be specific for some but not all of the IL-6–mediated signaling cascades in these cells.

scholarly journals Expression of interleukin-2 receptor on T cell chronic lymphocytic leukemia cells and their response to interleukin-2

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 316-321
Author(s):  
M Tsudo ◽  
T Uchiyama ◽  
H Umadome ◽  
Y Wano ◽  
T Hori ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Activated T Cells ◽  
Cell Chronic Lymphocytic Leukemia

We analyzed peripheral blood leukemic cells from six patients with T cell chronic lymphocytic leukemia (T-CLL) with monoclonal antibodies including the anti-Tac antibody, which recognizes the receptor for interleukin 2 (IL 2). The patients were divided into two groups according to the reactivity of the monoclonal antibodies. Leukemic cells from three patients with T-CLL reacted with OKT3 and T4 but not T8, whereas those from the remaining three patients reacted with OKT3 and T8 but not T4. IL 2 receptor, which is expressed on activated T cells but not on resting T cells, was preferentially expressed on T4+ T- CLL cells. The IL 2 receptor on T4+ T-CLL cells was indistinguishable from that on normal activated T cells with respect to molecular weight and downregulation by the anti-Tac antibody. Moreover, fresh T4+ T-CLL cells, but not T8+ T-CLL cells, proliferated in response to exogenous IL 2 without prior activation, and this proliferation was inhibited by the anti-Tac antibody. These results suggest that malignant growth of T4+ T-CLL cells can be regulated by IL 2 not only in vitro but also in vivo.

Abstract 57: Costimulation Mediated T-cell Survival Excerbates Kawasaki Disease

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Leon Parsaud ◽  
Yasmin Moolani ◽  
Trang T Duong ◽  
Andrew C Lau ◽  
Garrett T Keong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
T Cells ◽  
Coronary Artery ◽  
T Cell ◽  
Kawasaki Disease ◽  
Cell Survival ◽  
Activated T Cells ◽  
Coronary Arteritis ◽  
T Cell Survival

Introduction: Kawasaki Disease (KD) is a multi-system vasculitis leading to coronary artery damage. Previous work has shown that co-stimulatory signals can rescue a subset of superantigen (SAg) reactive T-cells from apoptosis and one of the major pathways responsible for delivery of this co-stimulatory signal is CD28 signaling on T-cells. Lactobacillus casei cell wall extract (LCWE) contains a SAg among its active ingredients, leading to induction of coronary arteritis in mice that closely resembles human KD. Methods: Flow cytometry was used to measure the expression of pro-survival molecules and markers of apoptosis. In vivo studies were performed with C57BL/6 mice (4-5 weeks) injected i.p. with either LCWE, or LCWE and anti-4-1BB or Isotype control antibody. Cardiac tissue isolated, processed, stained and scored as per protocol. Gene expression analysis in KD patients was performed using the Illumina HumanHT-12v4. Results: Despite the fact that SAg-activated T-cells undergo apoptosis and are deleted, T-cells persist and are central to ongoing inflammation in affected arteries. Stimulation of CD28 leads to upregulation of pro-survival molecules cFLIP and BCLxL and reduction of caspase 3-annexinV double positive cells (markers of apoptosis) after SAg-stimulation, as detected by flow cytometry. In animals co-injected with anti-4-1BB (co-stimulation agonist), the incidence of coronary arteritis was dramatically increased to 94% compared to 54% with LCWE alone. Analysis of gene expression profile from 171 children with KD show elevated levels of molecules specific to the CD28 signaling cascade through Grb2, and VAV1 leading to the upregulation of Rac1 and CDC42, together with upregulation of pro-survival molecules cFLIP, MCL1 and NAIP. Interestingly, increased expression of cell survival molecules was associated with IVIG failure, with statistically significant elevation of NAIP and CDC42 and a trend towards increased expression for cFLIP and MCL, in IVIG non-responders compared to responders. Conclusions: Enhanced co-stimulation contributes to T-cell survival after SAg-stimulation leading to persistent coronary artery inflammation and poor treatment response in KD.

scholarly journals Expression of interleukin-2 receptor on T cell chronic lymphocytic leukemia cells and their response to interleukin-2

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 316-321 ◽  
Author(s):  
M Tsudo ◽  
T Uchiyama ◽  
H Umadome ◽  
Y Wano ◽  
T Hori ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Activated T Cells ◽  
Cell Chronic Lymphocytic Leukemia

Abstract We analyzed peripheral blood leukemic cells from six patients with T cell chronic lymphocytic leukemia (T-CLL) with monoclonal antibodies including the anti-Tac antibody, which recognizes the receptor for interleukin 2 (IL 2). The patients were divided into two groups according to the reactivity of the monoclonal antibodies. Leukemic cells from three patients with T-CLL reacted with OKT3 and T4 but not T8, whereas those from the remaining three patients reacted with OKT3 and T8 but not T4. IL 2 receptor, which is expressed on activated T cells but not on resting T cells, was preferentially expressed on T4+ T- CLL cells. The IL 2 receptor on T4+ T-CLL cells was indistinguishable from that on normal activated T cells with respect to molecular weight and downregulation by the anti-Tac antibody. Moreover, fresh T4+ T-CLL cells, but not T8+ T-CLL cells, proliferated in response to exogenous IL 2 without prior activation, and this proliferation was inhibited by the anti-Tac antibody. These results suggest that malignant growth of T4+ T-CLL cells can be regulated by IL 2 not only in vitro but also in vivo.

scholarly journals The Pim kinases control rapamycin-resistant T cell survival and activation

2005 ◽  
Vol 201 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Casey J. Fox ◽  
Peter S. Hammerman ◽  
Craig B. Thompson
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Growth And Survival ◽  
Pim Kinases ◽  
T Cell Survival

Although Pim-1 or Pim-2 can contribute to lymphoid transformation when overexpressed, the physiologic role of these kinases in the immune response is uncertain. We now report that T cells from Pim-1−/−Pim-2−/− animals display an unexpected sensitivity to the immunosuppressant rapamycin. Cytokine-induced Pim-1 and Pim-2 promote the rapamycin-resistant survival of lymphocytes. The endogenous function of the Pim kinases was not restricted to the regulation of cell survival. Like the rapamycin target TOR, the Pim kinases also contribute to the regulation of lymphocyte growth and proliferation. Although rapamycin has a minimal effect on wild-type T cell expansion in vitro and in vivo, it completely suppresses the response of Pim-1−/−Pim-2−/− cells. Thus, endogenous levels of the Pim kinases are required for T cells to mount an immune response in the presence of rapamycin. The existence of a rapamycin-insensitive pathway that regulates T cell growth and survival has important implications for understanding how rapamycin functions as an immunomodulatory drug and for the development of complementary immunotherapeutics.

scholarly journals IL-17RA-signaling modulates CD8+ T cell survival and exhaustion during Trypanosoma cruzi infection

2018 ◽  
Author(s):  
Jimena Tosello Boari ◽  
Cintia L. Araujo Furlan ◽  
Facundo Fiocca Vernengo ◽  
Constanza Rodriguez ◽  
María C. Ramello ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Trypanosoma Cruzi ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
T Cell Survival

AbstractThe IL-17 family contributes to host defense against many intracellular pathogens by mechanisms not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes and their survival and appropriate response is orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. Absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells while recombinant IL-17 in vitro down-regulated the pro-apoptotic protein BAD and promoted activated CD8+ T cell survival. Phenotypic, functional and trancriptomic profiling showed that T. cruzi-specific CD8+ T cells arising in IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi.

scholarly journals Absence of Vasoactive Intestinal Peptide Signaling Significantly Enhances T Cell Survival Following MCMV Infection Via Increased Expression of Bcl-2 and Bcl-XL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1028-1028
Author(s):  
Christopher T Petersen ◽  
Katarzyna Anna Darlak ◽  
Jian-Ming Li ◽  
Edmund K Waller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Western Blot ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Mcmv Infection ◽  
Time Points ◽  
Qrt Pcr ◽  
T Cell Survival

Abstract Background The nervous system's influence on immune responses has become increasingly appreciated following the identification of a variety of immunomodulatory products secreted from neurons. One such product, vasoactive intestinal peptide (VIP), has been identified as an anti-inflammatory mediator exerting effects on both the innate and adaptive arms of the immune system. Interference with this pathway through blocking the VIP receptors VPAC1 and VPAC2 has been demonstrated to enhance T cell responses to viral infection as well as cancer. VIP antagonism results in increased numbers of antigen-specific cells in the peripheral blood and a shift in the balance of co-stimulatory and co-inhibitory molecules towards a pro-inflammatory phenotype. The consequences of such effects are a reduction in viral load in a model of MCMV infection and a reduced tumor burden and increased survival in a model of lymphoma. Methods In order to better understand the molecular mechanisms underlying the effects of VIP absence or antagonism, we used the MCMV infection model. Male VIP WT and VIP KO mice were infected with 105 pfu MCMV ip and sacrificed at various time points. Spleens were harvested and T cells were FACS sorted based on the expression of activation markers. Expression of pro and anti-apoptotic molecules was assessed via Western blot. Expression of VIP and its receptor VPAC1 was determined using qRT-PCR of extracted mRNA. In vitro T cell proliferation was assessed using CFSE dilution of splenocytes stimulated with CD3/CD28 beads and IL-2. Results We first examined levels of VIP and VPAC1 over the course of MCMV infection via qRT-PCR of extracted mRNA. Expression of VIP and VPAC1 was found to change in response to infection with an initial decrease in the levels of VPAC1 followed by an increase back to baseline levels. The pattern of VIP expression was opposite with an initial increase followed by a decrease. In order to gain more mechanistic insight into the effects of VIP signaling in T cells during MCMV infection, activated splenic CD8 T cells from WT mice and mice lacking VIP were FACS sorted at various time points. Activated CD69+CD8+ T cells from KO mice expressed higher levels of the anti-apoptotic protein Bcl-XL both during the initial response and at the peak by Western blot (Figure 1). Intracellular staining revealed an increased frequency of Bcl-2-expressing CD8 T cells in KO mice at the peak of the response (Figure 1). Proliferation of CFSE-labeled CD8 T cells in response to in vitro CD3/CD28 stimulation was found to be identical in wild type and VIP knockout cells suggesting modified T cell survival rather than proliferation. The negative influence of VIP on T cell survival resulted in significantly higher T cell frequency and a significant increase in the absolute numbers of antigen-specific splenic CD8 T cells in knockout mice (Figure 2). These results provide further support for VIP antagonism as a viable option for th e enhancement of CD8 T cell-mediated immunity. Disclosures No relevant conflicts of interest to declare.

T Cell Lymphopenia in Rhoh−/− Mice Results from Combined Defects of T Cell Migration and IL-7-Regulated Naïve T Cell Homeostasis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 872-872
Author(s):  
ShuShun Li ◽  
David A. Hildeman ◽  
H. Leighton Grimes ◽  
David A. Williams ◽  
Yi Gu
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Cell Survival ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
T Cell Migration ◽  
T Cell Lymphopenia ◽  
T Cell Survival

Abstract The Rho family GTPases are increasingly implicated for their important roles in T cell development and function. We have found that RhoH, a hematopoietic-specific member of this family is essential for thymocyte development (Gu et al, Nat Immunol, in press). Further, Rhoh−/− mice showed T cell lymphopenia. In particular, naïve T cells were reduced in secondary lymphoid organs and blood both in unchallenged and LCMV-challenged Rhoh−/− mice compared to WT controls. These findings suggest a possible defect in T cell emigration from thymus and peripheral T cell homeostasis in Rhoh−/− mice. To study the role(s) of RhoH in T cell migration and homeostasis, purified splenic T cells were adoptively transferred into common γ−/−; Rag2−/− mice. T cells were then recovered from spleens 3d and 8d post-transplantation. The recovery of Rhoh−/− T cells was decreased by 60% compared with WT cells. In vitro migration of Rhoh−/− T cells towards SDF-1α, a homeostatic chemokine for T cells, in a transwell migration assay was significantly reduced compared to WT cells. Flow analysis showed decreased number of CXCR4 expressing and reduced expression levels of CXCR4 on Rhoh−/− T cells. Furthermore, apoptotic T cells were increased twofold in Rhoh−/− mice compared to controls. CFSE staining of adoptively transferred T cells demonstrated a comparable proliferation rate between Rhoh−/− and WT cells in the recipient mice. Our data suggest that RhoH plays an important role in T cell homeostasis via regulating cell survival and SDF-1α-mediated migration. To further investigate how RhoH regulates T cell survival, we focused on IL-7, an essential factor for prolonged survival of naïve T cells. One way IL-7 exerts its effect is through upregulating the Bcl-2 family of antiapoptotic proteins. Our data showed that in vitro survival of Rhoh−/− T cells in response to IL-7 was impaired, and expression of IL-7Rα and Bcl-2 were both decreased in Rhoh−/− T cells. To further study a potential role of RhoH in regulation of IL-7R expression, FACsvantage sorted naïve T cells (CD4+CD44low, or CD8+CD44low) were cytokine starved overnight, then cultured with or without the addition of IL-7 for 6 hrs, and analyzed for IL-7Rα expression by flow cytometry. In WT cells, during cytokine starvation CD4 and a subset of CD8 naïve cells upregulated IL-7Rα expression, but this upregulation was reduced followed IL-7 stimulation. In contrast, Rhoh−/− T cells failed to show either up- or subsequent down-regulation of IL-7Rα in response to cytokine starvation and IL-7 exposure. These data may indicate a role for RhoH in regulating IL-7R expression in naïve CD4 T cells. Taken together, these findings suggest that RhoH is required for IL-7-mediated T cell survival and SDF-1α-mediated homing and/or emigration from thymus. Thus, deficiency of naïve T cells in Rhoh−/− mice likely results from combined defects in T cell migration and homeostasis.

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