L-Asparaginase II Produced by Salmonella Typhimurium Inhibits T Cell Responses and Mediates Virulence

Salmonella enterica serovar Typhimurium avoids clearance by the host immune system by suppressing T cell responses; however, the mechanisms that mediate this immunosuppression remain unknown. We show that S. Typhimurium inhibit T cell responses by producing L-Asparaginase II, which catalyzes the hyd...

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Bibliographic Details
Published in:Cell host & microbe 2012-12, Vol.12 (6), p.791-798
Main Authors: Kullas, Amy L., McClelland, Michael, Yang, Hee-Jeong, Tam, Jason W., Torres, AnnMarie, Porwollik, Steffen, Mena, Patricio, McPhee, Joseph B., Bogomolnaya, Lydia, Andrews-Polymenis, Helene, van der Velden, Adrianus W.M.
Format: Article
Language:English
Subjects:
Ammonia - metabolism
Animals
Asparaginase - genetics
Asparaginase - metabolism
Asparagine - metabolism
Aspartic Acid - metabolism
Cell Proliferation
Cytokines - metabolism
Gene Deletion
Immune Evasion
Mice
Mice, Inbred C57BL
Salmonella typhimurium - enzymology
Salmonella typhimurium - immunology
Salmonella typhimurium - pathogenicity
T-Lymphocytes - immunology
Virulence
Virulence Factors - genetics
Virulence Factors - metabolism
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Summary:Salmonella enterica serovar Typhimurium avoids clearance by the host immune system by suppressing T cell responses; however, the mechanisms that mediate this immunosuppression remain unknown. We show that S. Typhimurium inhibit T cell responses by producing L-Asparaginase II, which catalyzes the hydrolysis of L-asparagine to aspartic acid and ammonia. L-Asparaginase II is necessary and sufficient to suppress T cell blastogenesis, cytokine production, and proliferation and to downmodulate expression of the T cell receptor. Furthermore, S. Typhimurium-induced inhibition of T cells in vitro is prevented upon addition of L-asparagine. S. Typhimurium lacking the L-Asparaginase II gene (STM3106) are unable to inhibit T cell responses and exhibit attenuated virulence in vivo. L-Asparaginases are used to treat acute lymphoblastic leukemia through mechanisms that likely involve amino acid starvation of leukemic cells, and these findings indicate that pathogens similarly use L-asparagine deprivation to limit T cell responses. ► Salmonella utilize L-Asparaginase II to inhibit CD4+ and CD8+ T cells ► L-Asparaginase II of Salmonella is necessary and sufficient to cause T cell inhibition ► L-Asparaginase II inhibits blastogenesis, proliferation, and cytokine and TCR expression ► Salmonella lacking the L-Asparaginase II gene STM3106 (ansB) have attenuated virulence
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2012.10.018