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.

Reconstitution of T Cell Proliferation under Arginine Limitation: Activated Human T Cells Take Up Citrulline via L-Type Amino Acid Transporter 1 and Use It to Regenerate Arginine after Induction of Argininosuccinate Synthase Expression

“…Again, citrulline did rescue T cell proliferation only when a certain amount of extracellular arginine (optimal: 20 µM) was also present during T cell activation. As the production of the key inflammatory cytokine IFN-γ is critically dependent on arginine availability (11), we analyzed a potential effect of citrulline substitution on its secretion under various arginine conditions (Figure 1D). IFN-γ secretion was correlated with extracellular availability of arginine and was completely shut down in arginine-free conditions.…”

“…Arginase is localized intracellularly and/or is liberated into the extracellular space. In an arginine-deprived milieu, T cell proliferation is abolished (9) by inhibition of cell cycle progression in G 0 –G 1 phase (10), while T cell production of cytokines is either also impaired (e.g., IFN-γ) or largely unaffected (e.g., IL-2) (11, 12). As a consequence, inhibition of arginase-expressing MDSC (7) or supplementation of arginine to T cells (6) leads to increased efficiency of antitumoral T cells.…”

The prognostic value of the myeloid-mediated immunosuppression marker Arginase-1 in classic Hodgkin lymphoma

“…Arg-1 modifies the metabolism of L-arginine, including the de-phosphorylation of cofilin, which is needed for the stability of the immunological synapse [42] and downregulates the CD3ζ chain translation in T cells, contributing to inhibit T cell proliferation [19, 22, 29–31]. …”

The Prognostic Value of the Myeloid-Mediated Immunosuppression Marker Arginase-1 in Classic Hodgkin Lymphoma

“…Arg-1 is contained in neutrophils, at the level of cytoplasmic azurophil granules as reported in most cases [24,26,41] but also in gelatinase grains [25]. Arg-1 modifies the metabolism of L-arginine, including the dephosphorylation of cofilin, which is needed for the stability of the immunological synapse [42] and downregulates the CD3ζ chain translation in T cells, contributing to inhibit T cell proliferation [19,22,[29][30][31].…”