Martin Turner

Publications (63) View all

• Article: Pharmacological inhibition of glycogen synthase kinase 3 regulates T cell development in vitro.

  Jan-Hendrik Schroeder, Lewis S Bell, Michelle L Janas, Martin Turner
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  ABSTRACT: The development of functional T cells requires receptor-mediated transition through multiple checkpoints in the thymus. Double negative 3 (DN3) thymocytes are selected for the presence of a rearranged TCR beta chain in a process termed β-selection which requires signalling via the pre-TCR, Notch1 and CXCL12. Signal integration by these receptors converges on core pathways including the Phosphatidylinositol-3-kinase (PI3K) pathway. Glycogen Synthase Kinase 3 (GSK3) is generally thought to be negatively regulated by the PI3K pathway but its role in β-selection has not been characterised. Here we show that developmental progression of DN3 thymocytes is promoted following inhibition of GSK3 by the synthetic compound CHIR99021. CHIR99021 allows differentiation in the absence of pre-TCR-, Notch1- or CXCL12-mediated signalling. It antagonizes IL-7-mediated inhibition of DP thymocyte differentiation and increases IL-7-promoted cell recovery. These data indicate a potentially important role for inactivation of GSK3 during β-selection. They might help to establish an in vitro stromal cell-free culture system of thymocyte development and offer a new platform for screening regulators of proliferation, differentiation and apoptosis.
  PLoS ONE 01/2013; 8(3):e58501. · 4.09 Impact Factor
• Article: Pten loss in CD4 T cells enhances their helper function but does not lead to autoimmunity or lymphoma.

  Dalya R Soond, Fabien Garçon, Daniel T Patton, Julia Rolf, Martin Turner, Cheryl Scudamore, Oliver A Garden, Klaus Okkenhaug
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  ABSTRACT: PTEN, one of the most commonly mutated or lost tumor suppressors in human cancers, antagonizes signaling by the PI3K pathway. Mice with thymocyte-specific deletion of Pten rapidly develop peripheral lymphomas and autoimmunity, which may be caused by failed negative selection of thymocytes or from dysregulation of postthymic T cells. We induced conditional deletion of Pten from CD4 Th cells using a Cre knocked into the Tnfrsf4 (OX40) locus to generate OX40(Cre)Pten(f) mice. Pten-deficient Th cells proliferated more and produced greater concentrations of cytokines. The OX40(Cre)Pten(f) mice had a general increase in the number of lymphocytes in the lymph nodes, but not in the spleen. When transferred into wild-type (WT) mice, Pten-deficient Th cells enhanced anti-Listeria responses and the clearance of tumors under conditions in which WT T cells had no effect. Moreover, inflammatory responses were exaggerated and resolved later in OX40(Cre)Pten(f) mice than in WT mice. However, in contrast with models of thymocyte-specific Pten deletion, lymphomas and autoimmunity were not observed, even in older OX40(Cre)Pten(f) mice. Hence loss of Pten enhances Th cell function without obvious deleterious effects.
  The Journal of Immunology 05/2012; 188(12):5935-43. · 5.79 Impact Factor
• Article: An emerging role of RNA-binding proteins as multifunctional regulators of lymphocyte development and function.

  Martin Turner, Daniel J Hodson
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  ABSTRACT: Sequence-specific RNA-binding proteins (RBP) and the regulation of RNA decay have long been recognized as important regulators of the inflammatory response. RBP influence gene expression throughout the lifespan of the mRNA by regulating splicing, polyadenylation, cellular localization, translation, and decay. Increasing evidence now indicates that these proteins, together with the RNA decay machinery that they recruit, also regulate the development and activation of lymphocytes. The activity of RBP is regulated by the same signal transduction pathways that govern lymphocyte development and differentiation in response to antigen and cytokine receptor engagement. Roles for these proteins in regulating the diverse functions of lymphocytes are becoming increasingly apparent.
  Advances in Immunology 01/2012; 115:161-85. · 5.76 Impact Factor
• Article: Interaction of Ras with p110γ is required for thymic β-selection in the mouse.

  Michelle L Janas, Martin Turner
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  ABSTRACT: Thymocytes are tested for productive rearrangement of the tcrb locus by expression of a pre-TCR in a process termed β-selection, which requires both Notch1 and CXCR4 signaling. It has been shown that activation of the GTPase Ras allows thymocytes to proliferate and differentiate in the absence of a Pre-TCR; the direct targets of Ras at this checkpoint have not been identified, however. Mice with a mutant allele of p110γ unable to bind active Ras revealed that CXCR4-mediated PI3K activation is Ras dependent. The Ras-p110γ interaction was necessary for efficient β-selection-promoted proliferation but was dispensable for the survival or differentiation of thymocytes. Uncoupling Ras from p110γ provides unambiguous identification of a Ras interaction required for thymic β-selection.
  The Journal of Immunology 09/2011; 187(9):4667-75. · 5.79 Impact Factor
• Article: Stromal cell-derived factor 1α and CXCR4: newly defined requirements for efficient thymic β-selection.

  Michelle L Janas, Martin Turner
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  ABSTRACT: The progressive maturation of T cells is accompanied by their migration through the thymus, with each selection stage occurring in distinct microenvironments. Many specialized receptor-ligand pairs have been defined that drive T cell differentiation, but our understanding of the complex relationship between T cells and the thymic stroma is incomplete. Recent reports have identified a role for the chemokine stromal cell-derived factor 1α and its receptor CXC chemokine receptor 4 in β-selection. This review explores these findings in detail.
  Trends in Immunology 10/2010; 31(10):370-6. · 10.40 Impact Factor