title: Arginine deficiency leads to impaired cofilin dephosphorylation in activated human T lymphocytes.
abstract: The amino acid arginine is fundamentally involved in the regulation of the immune response during infection, inflammatory diseases and tumor growth. Arginine deficiency (e.g. due to the myeloid cell enzyme arginase) inhibits proliferation and effector functions of activated T lymphocytes. Here, we studied intracellular mechanisms mediating this suppression of human T lymphocytes. Our proteomic analysis revealed an impaired dephosphorylation of the actin-binding protein cofilin upon T-cell activation in the absence of arginine. We show that this correlates with alteration of actin polymerization and impaired accumulation of CD2 and CD3 in the evolving immunological synapse in T cell-antigen presenting cells conjugates. In contrast, T-cell cytokine synthesis is differentially regulated in human T lymphocytes in the absence of arginine. While the production of certain cytokines (e.g. IFN-γ) is severely reduced, T lymphocytes produce other cytokines (e.g. IL-2) independent of extracellular arginine. MEK and PI3K activity are reciprocally regulated in association with impaired cofilin dephosphorylation. Finally, we show that impaired cofilin dephosphorylation is also detectable in human T cells activated in a granulocyte-dominated purulent micromilieu due to arginase-mediated arginine depletion. Our novel results identify cofilin as a potential regulator of human T-cell activation under conditions of inflammatory arginine deficiency.
authors.affiliation: Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Feldmeyer
authors.forename: Guido
authors.initials: G
authors.lastname: Wabnitz
authors.forename: Stefan
authors.initials: S
authors.lastname: Leicht
authors.forename: Claudia
authors.initials: C
authors.lastname: Luckner-Minden
authors.forename: Martin
authors.initials: M
authors.lastname: Schiller
authors.forename: Thomas
authors.initials: T
authors.lastname: Franz
authors.forename: Roland
authors.initials: R
authors.lastname: Conradi
authors.forename: Pascale
authors.initials: P
authors.lastname: Kropf
authors.forename: Ingrid
authors.initials: I
authors.lastname: Müller
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Samstag
authors.forename: Markus
authors.initials: M
authors.lastname: Munder
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D001120:Arginine / Q000172:deficiency*; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D010766:Phosphorylation / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
chemical_list: D051339:Actin Depolymerizing Factors; D001120:Arginine