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.

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 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.

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.

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 IL-15 trans-presentation by pulmonary dendritic cells promotes effector CD8 T cell survival during influenza virus infection

2010 ◽  
Vol 207 (3) ◽  
pp. 521-534 ◽  
Author(s):  
Jodi McGill ◽  
Nico Van Rooijen ◽  
Kevin L. Legge
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Influenza Virus Infection ◽  
Cd8 T Cell ◽  
T Cell Survival

We have recently demonstrated that peripheral CD8 T cells require two separate activation hits to accumulate to high numbers in the lungs after influenza virus infection: a primary interaction with mature, antigen-bearing dendritic cells (DCs) in the lymph node, and a second, previously unrecognized interaction with MHC I–viral antigen–bearing pulmonary DCs in the lungs. We demonstrate that in the absence of lung-resident DC subsets, virus-specific CD8 T cells undergo significantly increased levels of apoptosis in the lungs; however, reconstitution with pulmonary plasmacytoid DCs and CD8α+ DCs promotes increased T cell survival and accumulation in the lungs. Further, our results show that the absence of DCs after influenza virus infection results in significantly reduced levels of IL-15 in the lungs and that pulmonary DC–mediated rescue of virus-specific CD8 T cell responses in the lungs requires trans-presentation of IL-15 via DC-expressed IL-15Rα. This study demonstrates a key, novel requirement for DC trans-presented IL-15 in promoting effector CD8 T cell survival in the respiratory tract after virus infection, and suggests that this trans-presentation could be an important target for the development of unique antiviral therapies and more effective vaccine strategies.

Histone Deacetylase 6 (HDAC6) Influences T-Cell Activation and Survival: Implications For Cancer Immunotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1050-1050
Author(s):  
Andressa Sodre Laino ◽  
David M Woods ◽  
Fengdong Cheng ◽  
Hongwei Wang ◽  
Eduardo M. Sotomayor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Wild Type ◽  
T Cell Survival

Abstract The role of histone deacetylases (HDACs) as epigenetic regulators of immune function is becoming increasingly clear. Recently, the role of specific HDACs in orchestrating T-cell maturation, survival and function has begun to emerge, giving rationale to selective therapy to direct immune responses in different disease settings, including cancer. In particular, HDAC6 has recently been characterized as a negative regulator of regulatory T-cell suppressive activity (de Zoeten, Molecular and Cellular Biology, 2011). Here we report an expanded, novel role of HDAC6 in regulating T-cell survival and activation. First, the relative expression of the eleven classic HDACs was evaluated in resting and activated T-cells from mouse and human samples. It was found that the majority of HDACs decrease in expression following activation, including HDAC6. Next, in a HDAC6KO mouse model, it was found that T-cells lacking HDAC6 had skewed survival when compared to wild-type murine T-cells. This difference seems to be the result of an increased CD4+ T-cells population in the lymph nodes, with a concomitant decrease in viable CD8+ T-cells. To determine whether this population skewing was the consequence of defects in HDAC6KO mice T-cell development, wild-type murine T-cells were treated with an isotype-selective HDAC6 inhibitor. The results seen in HDAC6KO T-cells were recapitulated when wild-type T-cells were activated and treated with HDAC6 specific inhibitors, indicating a role of HDAC6 outside of thymic development in promoting CD4+ T-cell survival at the expense of CD8+ T-cells. Interestingly, it was found that activated CD4+ T-cells displayed decreased expression of the apoptosis signaling receptor FAS after HDAC6 inhibition while no differences were observed in CD8+ T-cells under the same conditions. In addition to these results implicating HDAC6 in regulating T-cell survival, expression of surface markers was altered in both CD8+ and CD4+ T-cells, including enhanced expression of the activation molecule CD69 in stimulated T-cells treated with an isotype-selective HDAC6 inhibitor. Finally, in vivo studies in tumor-bearing HDAC6KO mice revealed a significantly delayed in tumor progression. Similar results were observed in lymphoma-bearing mice treated with HDAC6 specific inhibitors. Taken together, this data shows that HDACs are dynamic in expression with regards to T-cell activation state. More specifically, we have unveiled hereto-unexplored roles of HDAC6 in regulating T-cell survival and function, pointing at this specific HDAC as an appealing target to harness T-cell immunity in hematologic malignancies. Disclosures: No relevant conflicts of interest to declare.

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.

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.

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 CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

2002 ◽  
Vol 197 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Melanie S. Vacchio ◽  
Richard J. Hodes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
Cd8 Cells ◽  
Costimulatory Signal ◽  
Cd28 Costimulation

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

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