scholarly journals Cellular FLICE-inhibitory protein is required for T cell survival and cycling

2005 ◽  
Vol 202 (3) ◽  
pp. 405-413 ◽  
Author(s):  
Hien Chau ◽  
Veronica Wong ◽  
Nien-Jung Chen ◽  
Huey-Lan Huang ◽  
Wen-Jye Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cell Function ◽  
Embryonic Stem ◽  
Underlying Mechanism ◽  
Caspase 8 ◽  
Death Domain ◽  
Inhibitory Protein ◽  
T Cell Survival

Fas-associated death domain (FADD) and caspase-8 are key signal transducers for death receptor–induced apoptosis, whereas cellular FLICE-inhibitory protein (cFLIP) antagonizes this process. Interestingly, FADD and caspase-8 also play a role in T cell development and T cell receptor (TCR)–mediated proliferative responses. To investigate the underlying mechanism, we generated cFLIP-deficient T cells by reconstituting Rag−/− blastocysts with cFLIP-deficient embryonic stem cells. These Rag chimeric mutant mice (rcFLIP−/−) had severely reduced numbers of T cells in the thymus, lymph nodes, and spleen, although mature T lymphocytes did develop. Similar to FADD- or caspase-8–deficient cells, rcFLIP−/− T cells were impaired in proliferation in response to TCR stimulation. Further investigation revealed that cFLIP is required for T cell survival, as well as T cell cycling in response to TCR stimulation. Interestingly, some signaling pathways from the TCR complex appeared competent, as CD3 plus CD28 cross-linking was capable of activating the ERK pathway in rcFLIP−/− T cells. We demonstrate an essential role for cFLIP in T cell function.

scholarly journals Combined Deficiency of p50 and cRel in CD4+ T Cells Reveals an Essential Requirement for Nuclear Factor κB in Regulating Mature T Cell Survival and In Vivo Function

2003 ◽  
Vol 197 (7) ◽  
pp. 861-874 ◽  
Author(s):  
Ye Zheng ◽  
Monika Vig ◽  
Jesse Lyons ◽  
Luk Van Parijs ◽  
Amer A. Beg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Nuclear Factor ◽  
T Cell Function ◽  
T Cell Survival

Signaling pathways involved in regulating T cell proliferation and survival are not well understood. Here we have investigated a possible role of the nuclear factor (NF)-κB pathway in regulating mature T cell function by using CD4+ T cells from p50−/− cRel−/− mice, which exhibit virtually no inducible κB site binding activity. Studies with these mice indicate an essential role of T cell receptor (TCR)-induced NF-κB in regulating interleukin (IL)-2 expression, cell cycle entry, and survival of T cells. Our results further indicate that NF-κB regulates TCR-induced expression of antiapoptotic Bcl-2 family members. Strikingly, retroviral transduction of CD4+ T cells with the NF-κB–inducing IκB kinase β showed that NF-κB activation is not only necessary but also sufficient for T cell survival. In contrast, our results indicate a lack of involvement of NF-κB in both IL-2 and Akt-induced survival pathways. In vivo, p50−/− cRel−/− mice showed impaired superantigen-induced T cell responses as well as decreased numbers of effector/memory and regulatory CD4+ T cells. These findings provide the first demonstration of a role for NF-κB proteins in regulating T cell function in vivo and establish a critically important function of NF-κB in TCR-induced regulation of survival.

scholarly journals DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice

2011 ◽  
Vol 208 (11) ◽  
pp. 2305-2320 ◽  
Author(s):  
Katrina L. Randall ◽  
Stephanie S.-Y. Chan ◽  
Cindy S. Ma ◽  
Ivan Fung ◽  
Yan Mei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Viral Infections ◽  
Cd8 T Cell ◽  
T Cell Survival ◽  
And Function

In humans, DOCK8 immunodeficiency syndrome is characterized by severe cutaneous viral infections. Thus, CD8 T cell function may be compromised in the absence of DOCK8. In this study, by analyzing mutant mice and humans, we demonstrate a critical, intrinsic role for DOCK8 in peripheral CD8 T cell survival and function. DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA+CCR7− phenotype. Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic. DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division. Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall. These findings highlight a key role for DOCK8 in the survival and function of human and mouse CD8 T cells.

scholarly journals Interleukin-7 Regulates Bim Proapoptotic Activity in Peripheral T-Cell Survival

2009 ◽  
Vol 30 (3) ◽  
pp. 590-600 ◽  
Author(s):  
Wen Qing Li ◽  
Tad Guszczynski ◽  
Julie A. Hixon ◽  
Scott K. Durum
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
T Cell Development ◽  
Cell Development ◽  
Effector Memory ◽  
Intracellular Location ◽  
Interleukin 7 ◽  
Peripheral T Cells ◽  
T Cell Survival

ABSTRACT Interleukin-7 (IL-7) is critical for T-cell development and peripheral T-cell homeostasis. The survival of pro-T cells and mature T cells requires IL-7. The survival function of IL-7 is accomplished partly through induction of the antiapoptotic protein Bcl-2 and inhibition of proapoptotic proteins Bax and Bad. We show here that the proapoptotic protein Bim, a BH3-only protein belonging to the Bcl-2 family, also plays a role in peripheral T-cell survival. Deletion of Bim partially protected an IL-7-dependent T-cell line and peripheral T cells, especially cells with an effector memory phenotype, from IL-7 deprivation. However, T-cell development in the thymus was not restored in IL-7−/− Rag2−/− mice reconstituted with Bim−/− bone marrow. IL-7 withdrawal altered neither the intracellular location of Bim, which was constitutively mitochondrial, nor its association with Bcl-2; however, a reduction in its association with the prosurvival protein Mcl-1 was observed. IL-7 withdrawal did not increase Bim mRNA or protein expression but did induce changes in the isoelectric point of BimEL and its reactivity with an antiphosphoserine antibody. Our findings suggest that the maintenance of peripheral T cells by IL-7 occurs partly through inhibition of Bim activity at the posttranslational level.

scholarly journals Self–class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels

2009 ◽  
Vol 206 (10) ◽  
pp. 2253-2269 ◽  
Author(s):  
Kensuke Takada ◽  
Stephen C. Jameson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Class I ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
T Cell Survival ◽  
And Function

Previous studies have suggested that naive CD8 T cells require self-peptide–major histocompatability complex (MHC) complexes for maintenance. However, interpretation of such studies is complicated because of the involvement of lymphopenic animals, as lymphopenia drastically alters naive T cell homeostasis and function. In this study, we explored naive CD8 T cell survival and function in nonlymphopenic conditions by using bone marrow chimeric donors and hosts in which class I MHC expression is absent or limited to radiosensitive versus radioresistant cells. We found that long-term survival of naive CD8 T cells (but not CD4 T cells) was impaired in the absence of class I MHC. However, distinct from this effect, class I MHC deprivation also enhanced naive CD8 T cell responsiveness to low-affinity (but not high-affinity) peptide–MHC ligands. We found that this improved sensitivity was a consequence of up-regulated CD8 levels, which was mediated through a transcriptional mechanism. Hence, our data suggest that, in a nonlymphopenic setting, self-class I MHC molecules support CD8 T cell survival, but that these interactions also attenuate naive T cell sensitivity by dynamic tuning of CD8 levels.

scholarly journals Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells

2020 ◽  
Vol 117 (23) ◽  
pp. 12961-12968 ◽  
Author(s):  
M. Zeeshan Chaudhry ◽  
Rosaely Casalegno-Garduno ◽  
Katarzyna M. Sitnik ◽  
Bahram Kasmapour ◽  
Ann-Kathrin Pulm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Death Receptor ◽  
Cd8 T Cell ◽  
Cytotoxic T Cell ◽  
Caspase 8 ◽  
Infected Cells

Viral immune evasion is currently understood to focus on deflecting CD8 T cell recognition of infected cells by disrupting antigen presentation pathways. We evaluated viral interference with the ultimate step in cytotoxic T cell function, the death of infected cells. The viral inhibitor of caspase-8 activation (vICA) conserved in human cytomegalovirus (HCMV) and murine CMV (MCMV) prevents the activation of caspase-8 and proapoptotic signaling. We demonstrate the key role of vICA from either virus, in deflecting antigen-specific CD8 T cell-killing of infected cells. vICA-deficient mutants, lacking either UL36 or M36, exhibit greater susceptibility to CD8 T cell control than mutants lacking the set of immunoevasins known to disrupt antigen presentation via MHC class I. This difference is evident during infection in the natural mouse host infected with MCMV, in settings where virus-specific CD8 T cells are adoptively transferred. Finally, we identify the molecular mechanism through which vICA acts, demonstrating the central contribution of caspase-8 signaling at a point of convergence of death receptor-induced apoptosis and perforin/granzyme-dependent cytotoxicity.

scholarly journals CD4 T Cells Are Required for CD8 T Cell Survival during Both Primary and Memory Recall Responses

2007 ◽  
Vol 179 (12) ◽  
pp. 8243-8251 ◽  
Author(s):  
Patricia Novy ◽  
Michael Quigley ◽  
Xiaopei Huang ◽  
Yiping Yang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Memory Recall ◽  
T Cell Survival

Exploring the Biological Role of Kruppel-Like Factor 2 In Cytotoxic T Lymphocytes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2783-2783
Author(s):  
Gavin Charles Preston ◽  
Doreen A Cantrell
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Cell Survival ◽  
Cytotoxic T Lymphocytes ◽  
Adhesion Molecule ◽  
Cd8 T Cells ◽  
T Cell Memory ◽  
Transcriptional Program ◽  
T Cell Survival

Abstract Abstract 2783 Kruppel-like factor 2 (KLF2) is a transcription factor which has been shown to be a critical regulator of T lymphocyte quiescence and trafficking. KLF2 is highly expressed in naïve CD8 T cells but its expression is transcriptionally downregulated in effector cytotoxic T lymphocytes (CTL). To understand how KLF2 might co-ordinate biological processes in CTL, we have determined the impact of preventing KLF2 downregulation on the transcriptional program of antigen receptor triggered CD8 T cells. Our data show that CTL which fail to downregulate KLF2 have a strikingly different transcriptional program to normal CTL. Immune activated CD8 T cells that sustain KLF2 expression thus show increased expression of 672 genes and decreased expression of 205 genes compared to normal CTL that have lost KLF2. Previous studies have indicated that high levels of KLF2 correlate with long term T cell survival and the development of memory CD8 T cells. We therefore questioned whether the KLF2 regulated genes identified in our experiments gave any insight as to why increasing levels of KLF2 in immune activated T cells might control T cell memory. In this context, we noted that KLF2 downregulation is necessary for TCR triggering of the CTL mitotic pathway. The molecular basis for this effect includes that KLF2 drives expression of intracellular cell cycle inhibitors. It was equally striking, however, that KLF2 could induce expression of the inhibitory receptor Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (Ceacam1, CD66a), which can suppress the T cell proliferative response. The present report confirms that KLF2 controls the repertoire of chemokine receptors and adhesion molecules expressed by CTL. Previous studies have identified the adhesion molecule CD62L and the G protein coupled receptor S1P1 as direct gene targets for KLF2. The present data support that KLF2 positively regulates expression of these molecules but also describes a cell autonomous role for KLF2 to negatively regulate the expression of the inflammatory chemokine receptor CXCR3 in antigen primed CTL. The loss of KLF2 is thus essential to allow CTL to traffic to CXCR3 ligands. One other striking observation was that KLF2 expression in CTL upregulates expression of the IL-6 receptor and Serine Protease Inhibitor 6 (Spi6). The latter molecule has a key role in protecting CTL from self injury inflicted by granzymes and is critical for the generation of T cell memory. IL-6 receptor expression is similarly important for memory T cell survival. Collectively, these data identify new KLF2 regulated genes and biological functions in CD8 T cells and provide important insights as to how this transcription factor controls T cell immune responses and might determine the effector/memory fate of a CTL. Disclosures: No relevant conflicts of interest to declare.

Low Dose Interleukin-7 Supplementation Increases Intrinsic Cord Blood T Cell Survival without Enhancing Proliferative Alloresponses

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4353-4353
Author(s):  
Bánádicte Hivert ◽  
Laurent Benjamin Pascal ◽  
Jacques Trauet ◽  
Ibrahim Yakoub-Agha ◽  
Myriam Labalette
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Cell Survival ◽  
Low Dose ◽  
Acute Gvhd ◽  
Cell Compartment ◽  
Interleukin 7 ◽  
Cfse Dilution ◽  
T Cell Survival

Abstract Abstract 4353 Background: Umbilical cord blood (CB) transplantation is associated with delayed and defective immune reconstitution, in part because recent thymic emigrants, the most abundant subset among CB T cells, have limited intrinsic survival capacity. Interleukin-7 has been reported to increase the initial recovery of the graft-derived T cell compartment. The aim of this in vitro study was to define the optimal supplementation with recombinant human IL-7 (rhIL-7) than can promote the survival of CB T cells without enhancing allogeneic reactions, so as to limit the risk of eliciting an uncontrolled acute GVHD in vivo. Methods: Twenty-six CB were obtained immediately after normal-term delivery, using the same procedure as for CB banking, and a freeze-thawing step in order to recapitulate the clinical procedure. CB T cells were cultured for one week alone or with HLA-mismatched monocytes from healthy adults (MLR conditions), in medium supplemented or not with rhIL-7. Cell viability was assessed by flow cytometry by scatter analysis and 3,3'-dihexyloxacarbocyanine iodide [DiOC6(3)] and propidium iodide staining. CB T cell proliferation was assessed by CFSE dilution. Results: Under basic culture conditions, a unique high dose of rhIL-7 (1 ng/mL) added on day 0 improved CB T cell survival but also triggered their proliferation. A daily addition of a low dose of rhIL-7 (final concentration of 100 pg/mL) reduced CB T cell apoptosis and increased significantly cell survival after 1 week of culture (p <0.001), without inducing any cell proliferation. After one week of culture in allogeneic condition, small and large CB T cells were individualized on the cytogramm. Small cells corresponded to nonresponder CB T cells (CFSE dilution < 6,3%), while large CB T cells were allogeneic responder cells which underwent cell division. When allogeneic cultures were run with daily addition of rhIL-7 (100 pg/mL), the number of viable quiescent small CB T cells rose markedly (median 59,279 versus 36,726 without IL-7 supplementation, p=0.01), but the number of dividing cells among the large CB T cells did not increase significantly (median 29, 437 versus 24,471, p=0.19). Conclusion: These experimental data show that repeated exposition to low-doses of rhIL-7 can preserve a viable CB T cell compartment, potentially useful in CB transplantation both for T cell reconstitution and T cell recruitment after primary infections. In these IL-7 exposition conditions, recent thymic emigrants could survive better without undergoing an uncontrolled expansion that would be deleterious in increasing the risk of acute GVHD. These results indicate that clinical low dose IL-7 administration in umbilical cord blood transplanted patients, could improve post-transplant immune reconstitution, without potentiating risk of acute GVHD. Disclosures: No relevant conflicts of interest to declare.

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 (&lt;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.

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