Asparagine deprivation mediated by Salmonella asparaginase causes suppression of activation-induced T cell metabolic reprogramming

• DOI: 10.1189/jlb.4a0615-252r
• Publication Date: 2015-10-24T02:03:40Z
• Authors: AnnMarie Torres; Joanna D Luke; Amy L Kullas; Kanishk Kapilashrami; Yair Botbol; Antonius Koller; Peter J Tonge; Emily I Chen; Fernando Macian; Adrianus W M van ...
• Keywords: Salmonella typhimurium; Receptors, Antigen, T-Cell, alpha-beta; Molecular Sequence Data; Genes, myc; Lymphocyte Activation; 3. Good health; Mice, Inbred C57BL; Proto-Oncogene Proteins c-myc; Mice; 03 medical and health sciences; 0302 clinical medicine; Bacterial Proteins; T-Lymphocyte Subsets; Autophagy; Animals; Asparaginase; Interleukin-2; Female; Amino Acid Sequence; Lactic Acid; Asparagine; Cells, Cultured; Immune Evasion

Abstract Salmonellae are pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II l-asparaginase produced by Salmonella Typhimurium inhibits T cell responses and mediates virulence in a murine model of infection. Here, we report that this putative l-asparaginase exhibits l-asparagine hydrolase activity required for Salmonella Typhimurium to inhibit T cells. We show that l-asparagine is a nutrient important for T cell activation and that l-asparagine deprivation, such as that mediated by the Salmonella Typhimurium l-asparaginase, causes suppression of activation-induced mammalian target of rapamycin signaling, autophagy, Myc expression, and l-lactate secretion. We also show that l-asparagine deprivation mediated by the Salmonella Typhimurium l-asparaginase causes suppression of cellular processes and pathways involved in protein synthesis, metabolism, and immune response. Our results advance knowledge of a mechanism used by Salmonella Typhimurium to inhibit T cell responses and mediate virulence, and provide new insights into the prerequisites of T cell activation. We propose a model in which l-asparagine deprivation inhibits T cell exit from quiescence by causing suppression of activation-induced metabolic reprogramming.