Editors' ChoiceImmunometabolism

Activating T cells with asparagine

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Science Signaling  02 Feb 2021:
Vol. 14, Issue 668, eabg8244
DOI: 10.1126/scisignal.abg8244

Extracellular asparagine stimulates Lck to promote T cell responses to cancer cells and infection.

The abundance and lack of certain amino acids triggers metabolic signaling pathways. Wu et al. discovered a role for the nonessential amino acid asparagine in T cell function (see also Raynor and Chi). Asparagine supplementation enhanced the antigen-dependent activation, proliferation, and differentiation of CD8+ T cells in vitro. These effects were attenuated by the depletion of asparagine. Some tumor cell types secrete asparagine, and naïve CD8+ T cells cultured with medium conditioned by lymphoma or lung cancer cells showed increased activation. Mice fed an asparagine-deficient diet had decreased numbers of CD25+CD8+ T cells, activated CD4+ T cells, and central memory–like CD4+ and CD8+ T cells. Asparagine availability during an initial Listeria monocytogenes infection resulted in more CD8+ T cells expressing the proinflammatory cytokines IFN-γ and TNF-α during a second infection. Extracellular asparagine was taken up through the transporter SLC1A5, bound directly to Lck, a tyrosine kinase critical for T cell activation, and promoted the activation of Lck. When adoptively transferred, CD8+ T cells prestimulated with asparagine in vitro showed increased antitumor efficacy in mice injected with melanoma cells, which had smaller tumors and improved survival. Furthermore, these effects were mimicked by pretreatment of mice with asparagine before melanoma cell injection. Thus, extracellular asparagine stimulates Lck to promote T cell activation and responses to cancer cells and infection.

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