David Finlay | Trinity College Dublin (original) (raw)

Papers by David Finlay

Research paper thumbnail of mTORC1-Dependent Metabolic Reprogramming Is a Prerequisite for NK Cell Effector Function

The Journal of Immunology, 2014

The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cellular metabolism an... more The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cellular metabolism and also has fundamental roles in controlling immune responses. Emerging evidence suggests that these two functions of mTORC1 are integrally linked. However, little is known regarding mTORC1 function in controlling the metabolism and function of NK cells, lymphocytes that play key roles in antiviral and antitumor immunity. This study investigated the hypothesis that mTORC1-controlled metabolism underpins normal NK cell proinflammatory function. We demonstrate that mTORC1 is robustly stimulated in NK cells activated in vivo and in vitro. This mTORC1 activity is required for the production of the key NK cell effector molecules IFN-γ, which is important in delivering antimicrobial and immunoregulatory functions, and granzyme B, a critical component of NK cell cytotoxic granules. The data reveal that NK cells undergo dramatic metabolic reprogramming upon activation, upregulating rates of glucose uptake and glycolysis, and that mTORC1 activity is essential for attaining this elevated glycolytic state. Directly limiting the rate of glycolysis is sufficient to inhibit IFN-γ production and granzyme B expression. This study provides the highly novel insight that mTORC1-mediated metabolic reprogramming of NK cells is a prerequisite for the acquisition of normal effector functions.

Research paper thumbnail of PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells

Journal of Experimental Medicine, 2012

Research paper thumbnail of Protein Kinase B Controls Transcriptional Programs that Direct Cytotoxic T Cell Fate but Is Dispensable for T Cell Metabolism

Immunity, 2011

In cytotoxic T cells (CTL), Akt, also known as protein kinase B, is activated by the T cell antig... more In cytotoxic T cells (CTL), Akt, also known as protein kinase B, is activated by the T cell antigen receptor (TCR) and the cytokine interleukin 2 (IL-2). Akt can control cell metabolism in many cell types but whether this role is important for CTL function has not been determined. Here we have shown that Akt does not mediate IL-2-or TCR-induced cell metabolic responses; rather, this role is assumed by other Akt-related kinases. There is, however, a nonredundant role for sustained and strong activation of Akt in CTL to coordinate the TCR-and IL-2-induced transcriptional programs that control expression of key cytolytic effector molecules, adhesion molecules, and cytokine and chemokine receptors that distinguish effector versus memory and naive T cells. Akt is thus dispensable for metabolism, but the strength and duration of Akt activity dictates the CTL transcriptional program and determines CTL fate.

Research paper thumbnail of AMPKa1: an energy sensor determining CD8+ T cell memory responses

Research paper thumbnail of IRF4 links antigen affinity to CD8+ T-cell metabolism

Research paper thumbnail of Phosphoinositide 3-kinase and the mammalian target of rapamycin pathways control T cell migration

Annals of the New York Academy of Sciences, 2010

The established role for phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P 3 ) signaling path... more The established role for phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P 3 ) signaling pathways is to regulate cell metabolism. More recently it has emerged that PI(3,4,5)P 3 signaling via mammalian target of rapamycin and Foxo transcription factors also controls lymphocyte trafficking by determining the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. In quiescent T cells, nonphosphorylated active Foxos maintain expression of KLF2, a transcription factor that regulates expression of the chemokine receptors CCR7 and sphingosine 1 phosphate receptor, and the adhesion receptor CD62L that together control T-cell transmigration into secondary lymphoid tissues. PI(3,4,5)P 3 mediates activation of protein kinase B, which phosphorylates and inactivates Foxos, thereby terminating expression of KLF2 and its target genes. The correct localization of lymphocytes is essential for effective immune responses, and the ability of phosphoinositide 3-kinase and mammalian target of rapamycin to regulate expression of chemokine receptors and adhesion molecules puts these signaling molecules at the core of the molecular mechanisms that control lymphocyte trafficking.

Research paper thumbnail of Metabolism, migration and memory in cytotoxic T cells

Nature Reviews Immunology, 2011

The transcriptional and metabolic programs that control CD8 + T cells are regulated by a diverse ... more The transcriptional and metabolic programs that control CD8 + T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8 + T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metabolism and determine the effector versus memory fate of CD8 + T cells. We speculate that one link between metabolism and immunological memory is due to the acquired ability of kinases that evolved to control T cell metabolism to control the expression of key transcription factors that regulate CD8 + T cell effector function and migratory capacity. d.a.cantrell@dundee.ac.uk.

Research paper thumbnail of The coordination of T-cell function by serine/threonine kinases

The function of T-lymphocytes during adaptive immune responses is directed by antigen receptors, ... more The function of T-lymphocytes during adaptive immune responses is directed by antigen receptors, costimulatory molecules, and cytokines. These extrinsic stimuli are coupled to a network of serine/threonine kinases that control the epigenetic, transcriptional, and metabolic programs that determine T-cell function. It is increasingly recognized that serine/threonine kinases, notably those that are controlled by lipid second messengers such as polyunsaturated diacylglycerols (DAG) and phosphatidylinositol-(3,4,5)-trisphosphate (PIP 3 ), are at the core of T-cell signal transduction. In the present review the object will be to discuss some important examples of how pathways of serine/threonine phosphorylation control molecular functions of proteins and control protein localization to coordinate T-cell function in adaptive immune responses.

Research paper thumbnail of IRF4 links antigen affinity to CD8+ T-cell metabolism

Immunology and Cell Biology, 2014

Research paper thumbnail of Adenosine monophosphate-activated protein kinase regulates platelet-derived growth factor-BB-induced vascular smooth muscle cell migration

Archives of Biochemistry and Biophysics, 2013

Migration of vascular smooth muscle cells (VSMCs) is essential for repair of vascular injury, dev... more Migration of vascular smooth muscle cells (VSMCs) is essential for repair of vascular injury, development of atherosclerotic lesions and restenosis after angioplasty or by-pass graft surgery. It has been reported that platelet-derived growth factor (PDGF)-BB induces VSMC migration via the p44/p42 mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol 3 (PI3)-kinase/Akt pathway. Adenosine monophosphate-activated protein kinase (AMPK) is generally known to regulate multiple metabolic pathway. In the present study, we investigated the involvement of AMPK in PDGF-BB-induced migration of VSMCs using, a VSMC line, A10 cells. PDGF-BB induced phosphorylation of AMPK-α at Thr-172 residue. Treatment of A10 cells with compound C, an AMPK inhibitor, suppressed PDGF-BB-induced migration in a concentration-dependent manner (0.01-1μM). Compound C truly attenuated PDGF-BB induced phosphorylation of acetyl-CoA carboxylase, a downstream substance of AMPK. Downregulation of AMPK-α expression by the siRNA appeared an anti-migratory effect on PDGF-BB-induced migration. PDGF-BB-induced phosphorylation of c-Raf, MEK1/2 or p44/p42 MAP kinase, and phosphorylation of PI3-kinase or Akt were markedly suppressed by compound C. In conclusion, our results strongly suggest that PDGF-BB induces activation of AMPK in VSMCs, and subsequently regulates the migration via both the p44/p42 MAP kinase pathway and the PI3-kinase/Akt pathway.

Research paper thumbnail of Regulation of glucose metabolism in T cells: new insight into the role of Phosphoinositide 3-kinases

Frontiers in immunology, 2012

Naïve T cells are relatively quiescent cells that only require energy to prevent atrophy and for ... more Naïve T cells are relatively quiescent cells that only require energy to prevent atrophy and for survival and migration. However, in response to developmental or extrinsic cues T cells can engage in rapid growth and robust proliferation, produce of a range of effector molecules and migrate through peripheral tissues. To meet the significantly increased metabolic demands of these activities, T cells switch from primarily metabolizing glucose to carbon dioxide through oxidative phosphorylation to utilizing glycolysis to convert glucose to lactate (termed aerobic glycolysis). This metabolic switch allows glucose to be used as a source of carbon to generate biosynthetic precursors for the production of protein, DNA, and phospholipids, and is crucial for T cells to meet metabolic demands. Phosphoinositide 3-kinases (PI3K) are a family of inositol lipid kinases linked with a broad range of cellular functions in T lymphocytes that include cell growth, proliferation, metabolism, differentia...

Research paper thumbnail of mTORC1 regulates CD8 + T-cell glucose metabolism and function independently of PI3K and PKB

Biochemical Society Transactions, 2013

Given that inflammatory T-cells have a highly glycolytic metabolism, whereas regulatory T-cells r... more Given that inflammatory T-cells have a highly glycolytic metabolism, whereas regulatory T-cells rely more on oxidative glucose metabolism, there is growing interest in understanding how T-cell metabolism relates to T-cell function. The mTORC1 (mammalian target of rapamycin complex 1) has a crucial role to determine the balance between effector and regulatory T-cell differentiation, but is also described as a key regulator of metabolism in non-immune cell systems. The present review explores the relationship between these diverse functions of mTORC1 with regard to T-cell function. In many cell systems, mTORC1 couples PI3K (phosphoinositide 3-kinase) and PKB (protein kinase B), also known as Akt, with the control of glucose uptake and glycolysis. However, this is not the case in activated CD8+ CTLs (cytotoxic T-lymphocytes) where PI3K/PKB signalling is dispensable for the elevated levels of glycolysis that is characteristic of activated T-cells. Nevertheless, mTORC1 is still essential for glycolytic metabolism in CD8+ T-cells, and this reflects the fact that mTORC1 does not lie downstream of PI3K/PKB signalling in CD8+ T-cells, as is the case in many other cell systems. mTORC1 regulates glucose metabolism in CTLs through regulating the expression of the transcription factor HIF1α (hypoxia-inducible factor 1α). Strikingly, HIF1α functions to couple mTORC1 with a diverse transcriptional programme that extends beyond the control of glucose metabolism to the regulation of multiple key T-cell functions. The present review discusses the idea that mTORC1/HIF1α signalling integrates the control of T-cell metabolism and T-cell function.

Research paper thumbnail of A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression

Journal of molecular endocrinology, 2006

Insulin regulation of hepatic gene transcription is a vital component of glucose homeostasis. Und... more Insulin regulation of hepatic gene transcription is a vital component of glucose homeostasis. Understanding the molecular regulationof thisprocess aids the searchfor the defect(s) that promotesinsulin-resistant states, such asdiabetesmellitus. We havepreviously shownthat the insulin regulationof hepatic IGF-binding protein-1 (IGFBP1) expression requiresthe signalling proteins phosphatidylinositol 3-kinase (PI 3-kinase) and mammalian target of rapamycin (mTOR). In this report, we demonstrate that activation of the mTOR pathway, without activation of its upstream regulator PI 3-kinase, reduces IGFBP1 expression. Therefore, mTOR activation is sufficient to mimic insulin regulation of this gene. However, longer exposure (>3 h) of cells to insulin reduces the importance of this pathway in insulin regulation of the gene, suggesting a temporal switch in signalling mechanisms linking insulin action to the IGFBP1 gene promoter. In contrast, the activation of PI 3-kinase is required for in...

Research paper thumbnail of Europe PMC Funders Group

Research paper thumbnail of Adenosine-Mono-Phosphate-Activated Protein Kinase-Independent Effects of Metformin in T Cells

Research paper thumbnail of Notch-induced T cell development requires phosphoinositide-dependent kinase 1

The EMBO Journal, 2007

Phosphoinositide-dependent kinase l (PDK1) phosphorylates and activates multiple AGC serine kinas... more Phosphoinositide-dependent kinase l (PDK1) phosphorylates and activates multiple AGC serine kinases, including protein kinase B (PKB), p70Ribosomal S6 kinase (S6K) and p90Ribosomal S6 kinase (RSK). PDK1 is required for thymocyte differentiation and proliferation, and herein, we explore the molecular basis for these essential functions of PDK1 in T lymphocyte development. A key finding is that PDK1 is required for the expression of key nutrient receptors in T cell progenitors: CD71 the transferrin receptor and CD98 a subunit of L-amino acid transporters. PDK1 is also essential for Notch-mediated trophic and proliferative responses in thymocytes. A PDK1 mutant PDK1 L155E, which supports activation of PKB but no other AGC kinases, can restore CD71 and CD98 expression in pre-T cells and restore thymocyte differentiation. However, PDK1 L155E is insufficient for thymocyte proliferation. The role of PDK1 in thymus development thus extends beyond its ability to regulate PKB. In addition, PDK1 phosphorylation of AGC kinases such as S6K and RSK is also necessary for thymocyte development.

Research paper thumbnail of T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR

Proceedings of the National Academy of Sciences, 2008

Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinan... more Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinants of the Treg cell fate are not completely understood, we have delineated signaling events that control the de novo expression of Foxp3 in naive peripheral CD4 T cells and in thymocytes. We report that premature termination of TCR signaling and inibition of phosphatidyl inositol 3-kinase (PI3K) p110␣, p110␦, protein kinase B (Akt), or mammalian target of rapamycin (mTOR) conferred Foxp3 expression and Treglike gene expression profiles. Conversely, continued TCR signaling and constitutive PI3K/Akt/mTOR activity antagonised Foxp3 induction. At the chromatin level, di-and trimethylation of lysine 4 of histone H3 (H3K4me2 and -3) near the Foxp3 transcription start site (TSS) and within the 5 untranslated region (UTR) preceded active Foxp3 expression and, like Foxp3 inducibility, was lost upon continued TCR stimulation. These data demonstrate that the PI3K/ Akt/mTOR signaling network regulates Foxp3 expression.

Research paper thumbnail of Corrigendum: Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking

Nature Immunology, 2008

PI3K and mTOR are evolutionarily conserved regulators of cell metabolism. Here we show PI3K and m... more PI3K and mTOR are evolutionarily conserved regulators of cell metabolism. Here we show PI3K and mTOR determine the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. Key lymph node homing receptors, CD62L (L-selectin) and CCR7, are highly expressed on naive T lymphocytes but downregulated following immune activation. CD62L downregulation occurs via ectodomain proteolysis and suppression of gene transcription. PI3K p110 controls CD62L proteolysis via mitogen-activated protein (MAP) kinases whereas PI3K p110 control of CD62L transcription is mediated by the nutrient sensor mTOR via regulation of the transcription factor KLF2. PI3K-mTOR nutrient sensing pathways also determined expression of the chemokine receptor CCR7 and regulate lymphocyte trafficking in vivo. Hence, lymphocytes utilize PI3K and mTOR to match metabolism and trafficking.

Research paper thumbnail of Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking

Nature Immunology, 2008

PI3K and mTOR are evolutionarily conserved regulators of cell metabolism. Here we show PI3K and m... more PI3K and mTOR are evolutionarily conserved regulators of cell metabolism. Here we show PI3K and mTOR determine the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. Key lymph node homing receptors, CD62L (L-selectin) and CCR7, are highly expressed on naive T lymphocytes but downregulated following immune activation. CD62L downregulation occurs via ectodomain proteolysis and suppression of gene transcription. PI3K p110δ controls CD62L proteolysis via mitogen-activated protein (MAP) kinases whereas PI3K p110δ control of CD62L transcription is mediated by the nutrient sensor mTOR via regulation of the transcription factor KLF2. PI3K-mTOR nutrient sensing pathways also determined expression of the chemokine receptor CCR7 and regulate lymphocyte trafficking in vivo. Hence, lymphocytes utilize PI3K and mTOR to match metabolism and trafficking.

Research paper thumbnail of Phosphoinositide (3,4,5)-Triphosphate Binding to Phosphoinositide-Dependent Kinase 1 Regulates a Protein Kinase B/Akt Signaling Threshold That Dictates T-Cell Migration, Not Proliferation

Molecular and Cellular Biology, 2009

Research paper thumbnail of mTORC1-Dependent Metabolic Reprogramming Is a Prerequisite for NK Cell Effector Function

The Journal of Immunology, 2014

The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cellular metabolism an... more The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cellular metabolism and also has fundamental roles in controlling immune responses. Emerging evidence suggests that these two functions of mTORC1 are integrally linked. However, little is known regarding mTORC1 function in controlling the metabolism and function of NK cells, lymphocytes that play key roles in antiviral and antitumor immunity. This study investigated the hypothesis that mTORC1-controlled metabolism underpins normal NK cell proinflammatory function. We demonstrate that mTORC1 is robustly stimulated in NK cells activated in vivo and in vitro. This mTORC1 activity is required for the production of the key NK cell effector molecules IFN-γ, which is important in delivering antimicrobial and immunoregulatory functions, and granzyme B, a critical component of NK cell cytotoxic granules. The data reveal that NK cells undergo dramatic metabolic reprogramming upon activation, upregulating rates of glucose uptake and glycolysis, and that mTORC1 activity is essential for attaining this elevated glycolytic state. Directly limiting the rate of glycolysis is sufficient to inhibit IFN-γ production and granzyme B expression. This study provides the highly novel insight that mTORC1-mediated metabolic reprogramming of NK cells is a prerequisite for the acquisition of normal effector functions.

Research paper thumbnail of PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells

Journal of Experimental Medicine, 2012

Research paper thumbnail of Protein Kinase B Controls Transcriptional Programs that Direct Cytotoxic T Cell Fate but Is Dispensable for T Cell Metabolism

Immunity, 2011

In cytotoxic T cells (CTL), Akt, also known as protein kinase B, is activated by the T cell antig... more In cytotoxic T cells (CTL), Akt, also known as protein kinase B, is activated by the T cell antigen receptor (TCR) and the cytokine interleukin 2 (IL-2). Akt can control cell metabolism in many cell types but whether this role is important for CTL function has not been determined. Here we have shown that Akt does not mediate IL-2-or TCR-induced cell metabolic responses; rather, this role is assumed by other Akt-related kinases. There is, however, a nonredundant role for sustained and strong activation of Akt in CTL to coordinate the TCR-and IL-2-induced transcriptional programs that control expression of key cytolytic effector molecules, adhesion molecules, and cytokine and chemokine receptors that distinguish effector versus memory and naive T cells. Akt is thus dispensable for metabolism, but the strength and duration of Akt activity dictates the CTL transcriptional program and determines CTL fate.

Research paper thumbnail of AMPKa1: an energy sensor determining CD8+ T cell memory responses

Research paper thumbnail of IRF4 links antigen affinity to CD8+ T-cell metabolism

Research paper thumbnail of Phosphoinositide 3-kinase and the mammalian target of rapamycin pathways control T cell migration

Annals of the New York Academy of Sciences, 2010

The established role for phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P 3 ) signaling path... more The established role for phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P 3 ) signaling pathways is to regulate cell metabolism. More recently it has emerged that PI(3,4,5)P 3 signaling via mammalian target of rapamycin and Foxo transcription factors also controls lymphocyte trafficking by determining the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. In quiescent T cells, nonphosphorylated active Foxos maintain expression of KLF2, a transcription factor that regulates expression of the chemokine receptors CCR7 and sphingosine 1 phosphate receptor, and the adhesion receptor CD62L that together control T-cell transmigration into secondary lymphoid tissues. PI(3,4,5)P 3 mediates activation of protein kinase B, which phosphorylates and inactivates Foxos, thereby terminating expression of KLF2 and its target genes. The correct localization of lymphocytes is essential for effective immune responses, and the ability of phosphoinositide 3-kinase and mammalian target of rapamycin to regulate expression of chemokine receptors and adhesion molecules puts these signaling molecules at the core of the molecular mechanisms that control lymphocyte trafficking.

Research paper thumbnail of Metabolism, migration and memory in cytotoxic T cells

Nature Reviews Immunology, 2011

The transcriptional and metabolic programs that control CD8 + T cells are regulated by a diverse ... more The transcriptional and metabolic programs that control CD8 + T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8 + T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metabolism and determine the effector versus memory fate of CD8 + T cells. We speculate that one link between metabolism and immunological memory is due to the acquired ability of kinases that evolved to control T cell metabolism to control the expression of key transcription factors that regulate CD8 + T cell effector function and migratory capacity. d.a.cantrell@dundee.ac.uk.

Research paper thumbnail of The coordination of T-cell function by serine/threonine kinases

The function of T-lymphocytes during adaptive immune responses is directed by antigen receptors, ... more The function of T-lymphocytes during adaptive immune responses is directed by antigen receptors, costimulatory molecules, and cytokines. These extrinsic stimuli are coupled to a network of serine/threonine kinases that control the epigenetic, transcriptional, and metabolic programs that determine T-cell function. It is increasingly recognized that serine/threonine kinases, notably those that are controlled by lipid second messengers such as polyunsaturated diacylglycerols (DAG) and phosphatidylinositol-(3,4,5)-trisphosphate (PIP 3 ), are at the core of T-cell signal transduction. In the present review the object will be to discuss some important examples of how pathways of serine/threonine phosphorylation control molecular functions of proteins and control protein localization to coordinate T-cell function in adaptive immune responses.

Research paper thumbnail of IRF4 links antigen affinity to CD8+ T-cell metabolism

Immunology and Cell Biology, 2014

Research paper thumbnail of Adenosine monophosphate-activated protein kinase regulates platelet-derived growth factor-BB-induced vascular smooth muscle cell migration

Archives of Biochemistry and Biophysics, 2013

Migration of vascular smooth muscle cells (VSMCs) is essential for repair of vascular injury, dev... more Migration of vascular smooth muscle cells (VSMCs) is essential for repair of vascular injury, development of atherosclerotic lesions and restenosis after angioplasty or by-pass graft surgery. It has been reported that platelet-derived growth factor (PDGF)-BB induces VSMC migration via the p44/p42 mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol 3 (PI3)-kinase/Akt pathway. Adenosine monophosphate-activated protein kinase (AMPK) is generally known to regulate multiple metabolic pathway. In the present study, we investigated the involvement of AMPK in PDGF-BB-induced migration of VSMCs using, a VSMC line, A10 cells. PDGF-BB induced phosphorylation of AMPK-α at Thr-172 residue. Treatment of A10 cells with compound C, an AMPK inhibitor, suppressed PDGF-BB-induced migration in a concentration-dependent manner (0.01-1μM). Compound C truly attenuated PDGF-BB induced phosphorylation of acetyl-CoA carboxylase, a downstream substance of AMPK. Downregulation of AMPK-α expression by the siRNA appeared an anti-migratory effect on PDGF-BB-induced migration. PDGF-BB-induced phosphorylation of c-Raf, MEK1/2 or p44/p42 MAP kinase, and phosphorylation of PI3-kinase or Akt were markedly suppressed by compound C. In conclusion, our results strongly suggest that PDGF-BB induces activation of AMPK in VSMCs, and subsequently regulates the migration via both the p44/p42 MAP kinase pathway and the PI3-kinase/Akt pathway.

Research paper thumbnail of Regulation of glucose metabolism in T cells: new insight into the role of Phosphoinositide 3-kinases

Frontiers in immunology, 2012

Naïve T cells are relatively quiescent cells that only require energy to prevent atrophy and for ... more Naïve T cells are relatively quiescent cells that only require energy to prevent atrophy and for survival and migration. However, in response to developmental or extrinsic cues T cells can engage in rapid growth and robust proliferation, produce of a range of effector molecules and migrate through peripheral tissues. To meet the significantly increased metabolic demands of these activities, T cells switch from primarily metabolizing glucose to carbon dioxide through oxidative phosphorylation to utilizing glycolysis to convert glucose to lactate (termed aerobic glycolysis). This metabolic switch allows glucose to be used as a source of carbon to generate biosynthetic precursors for the production of protein, DNA, and phospholipids, and is crucial for T cells to meet metabolic demands. Phosphoinositide 3-kinases (PI3K) are a family of inositol lipid kinases linked with a broad range of cellular functions in T lymphocytes that include cell growth, proliferation, metabolism, differentia...

Research paper thumbnail of mTORC1 regulates CD8 + T-cell glucose metabolism and function independently of PI3K and PKB

Biochemical Society Transactions, 2013

Given that inflammatory T-cells have a highly glycolytic metabolism, whereas regulatory T-cells r... more Given that inflammatory T-cells have a highly glycolytic metabolism, whereas regulatory T-cells rely more on oxidative glucose metabolism, there is growing interest in understanding how T-cell metabolism relates to T-cell function. The mTORC1 (mammalian target of rapamycin complex 1) has a crucial role to determine the balance between effector and regulatory T-cell differentiation, but is also described as a key regulator of metabolism in non-immune cell systems. The present review explores the relationship between these diverse functions of mTORC1 with regard to T-cell function. In many cell systems, mTORC1 couples PI3K (phosphoinositide 3-kinase) and PKB (protein kinase B), also known as Akt, with the control of glucose uptake and glycolysis. However, this is not the case in activated CD8+ CTLs (cytotoxic T-lymphocytes) where PI3K/PKB signalling is dispensable for the elevated levels of glycolysis that is characteristic of activated T-cells. Nevertheless, mTORC1 is still essential for glycolytic metabolism in CD8+ T-cells, and this reflects the fact that mTORC1 does not lie downstream of PI3K/PKB signalling in CD8+ T-cells, as is the case in many other cell systems. mTORC1 regulates glucose metabolism in CTLs through regulating the expression of the transcription factor HIF1α (hypoxia-inducible factor 1α). Strikingly, HIF1α functions to couple mTORC1 with a diverse transcriptional programme that extends beyond the control of glucose metabolism to the regulation of multiple key T-cell functions. The present review discusses the idea that mTORC1/HIF1α signalling integrates the control of T-cell metabolism and T-cell function.

Research paper thumbnail of A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression

Journal of molecular endocrinology, 2006

Insulin regulation of hepatic gene transcription is a vital component of glucose homeostasis. Und... more Insulin regulation of hepatic gene transcription is a vital component of glucose homeostasis. Understanding the molecular regulationof thisprocess aids the searchfor the defect(s) that promotesinsulin-resistant states, such asdiabetesmellitus. We havepreviously shownthat the insulin regulationof hepatic IGF-binding protein-1 (IGFBP1) expression requiresthe signalling proteins phosphatidylinositol 3-kinase (PI 3-kinase) and mammalian target of rapamycin (mTOR). In this report, we demonstrate that activation of the mTOR pathway, without activation of its upstream regulator PI 3-kinase, reduces IGFBP1 expression. Therefore, mTOR activation is sufficient to mimic insulin regulation of this gene. However, longer exposure (>3 h) of cells to insulin reduces the importance of this pathway in insulin regulation of the gene, suggesting a temporal switch in signalling mechanisms linking insulin action to the IGFBP1 gene promoter. In contrast, the activation of PI 3-kinase is required for in...

Research paper thumbnail of Europe PMC Funders Group

Research paper thumbnail of Adenosine-Mono-Phosphate-Activated Protein Kinase-Independent Effects of Metformin in T Cells

Research paper thumbnail of Notch-induced T cell development requires phosphoinositide-dependent kinase 1

The EMBO Journal, 2007

Phosphoinositide-dependent kinase l (PDK1) phosphorylates and activates multiple AGC serine kinas... more Phosphoinositide-dependent kinase l (PDK1) phosphorylates and activates multiple AGC serine kinases, including protein kinase B (PKB), p70Ribosomal S6 kinase (S6K) and p90Ribosomal S6 kinase (RSK). PDK1 is required for thymocyte differentiation and proliferation, and herein, we explore the molecular basis for these essential functions of PDK1 in T lymphocyte development. A key finding is that PDK1 is required for the expression of key nutrient receptors in T cell progenitors: CD71 the transferrin receptor and CD98 a subunit of L-amino acid transporters. PDK1 is also essential for Notch-mediated trophic and proliferative responses in thymocytes. A PDK1 mutant PDK1 L155E, which supports activation of PKB but no other AGC kinases, can restore CD71 and CD98 expression in pre-T cells and restore thymocyte differentiation. However, PDK1 L155E is insufficient for thymocyte proliferation. The role of PDK1 in thymus development thus extends beyond its ability to regulate PKB. In addition, PDK1 phosphorylation of AGC kinases such as S6K and RSK is also necessary for thymocyte development.

Research paper thumbnail of T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR

Proceedings of the National Academy of Sciences, 2008

Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinan... more Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinants of the Treg cell fate are not completely understood, we have delineated signaling events that control the de novo expression of Foxp3 in naive peripheral CD4 T cells and in thymocytes. We report that premature termination of TCR signaling and inibition of phosphatidyl inositol 3-kinase (PI3K) p110␣, p110␦, protein kinase B (Akt), or mammalian target of rapamycin (mTOR) conferred Foxp3 expression and Treglike gene expression profiles. Conversely, continued TCR signaling and constitutive PI3K/Akt/mTOR activity antagonised Foxp3 induction. At the chromatin level, di-and trimethylation of lysine 4 of histone H3 (H3K4me2 and -3) near the Foxp3 transcription start site (TSS) and within the 5 untranslated region (UTR) preceded active Foxp3 expression and, like Foxp3 inducibility, was lost upon continued TCR stimulation. These data demonstrate that the PI3K/ Akt/mTOR signaling network regulates Foxp3 expression.

Research paper thumbnail of Corrigendum: Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking

Nature Immunology, 2008

PI3K and mTOR are evolutionarily conserved regulators of cell metabolism. Here we show PI3K and m... more PI3K and mTOR are evolutionarily conserved regulators of cell metabolism. Here we show PI3K and mTOR determine the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. Key lymph node homing receptors, CD62L (L-selectin) and CCR7, are highly expressed on naive T lymphocytes but downregulated following immune activation. CD62L downregulation occurs via ectodomain proteolysis and suppression of gene transcription. PI3K p110 controls CD62L proteolysis via mitogen-activated protein (MAP) kinases whereas PI3K p110 control of CD62L transcription is mediated by the nutrient sensor mTOR via regulation of the transcription factor KLF2. PI3K-mTOR nutrient sensing pathways also determined expression of the chemokine receptor CCR7 and regulate lymphocyte trafficking in vivo. Hence, lymphocytes utilize PI3K and mTOR to match metabolism and trafficking.

Research paper thumbnail of Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking

Nature Immunology, 2008

PI3K and mTOR are evolutionarily conserved regulators of cell metabolism. Here we show PI3K and m... more PI3K and mTOR are evolutionarily conserved regulators of cell metabolism. Here we show PI3K and mTOR determine the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. Key lymph node homing receptors, CD62L (L-selectin) and CCR7, are highly expressed on naive T lymphocytes but downregulated following immune activation. CD62L downregulation occurs via ectodomain proteolysis and suppression of gene transcription. PI3K p110δ controls CD62L proteolysis via mitogen-activated protein (MAP) kinases whereas PI3K p110δ control of CD62L transcription is mediated by the nutrient sensor mTOR via regulation of the transcription factor KLF2. PI3K-mTOR nutrient sensing pathways also determined expression of the chemokine receptor CCR7 and regulate lymphocyte trafficking in vivo. Hence, lymphocytes utilize PI3K and mTOR to match metabolism and trafficking.

Research paper thumbnail of Phosphoinositide (3,4,5)-Triphosphate Binding to Phosphoinositide-Dependent Kinase 1 Regulates a Protein Kinase B/Akt Signaling Threshold That Dictates T-Cell Migration, Not Proliferation

Molecular and Cellular Biology, 2009