Coordination of asparagine uptake and asparagine synthetase expression modulates CD8<sup>+</sup> T cell activation

Helen Carrasco Hope; Rebecca J. Brownlie; Christopher M. Fife; Lynette Steele; Mihaela Lorger; Robert J. Salmond

doi:10.1172/jci.insight.137761

Coordination of asparagine uptake and asparagine synthetase expression modulates CD8⁺ T cell activation

Helen Carrasco Hope,¹ Rebecca J. Brownlie,¹ Christopher M. Fife,¹ Lynette Steele,¹ Mihaela Lorger,¹ and Robert J. Salmond²

Published April 6, 2021 - More info

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Abstract

T cell receptor (TCR) triggering by antigen results in metabolic reprogramming that, in turn, facilitates T cells’ exit from quiescence. The increased nutrient requirements of activated lymphocytes are met in part by upregulation of cell surface transporters and enhanced uptake of amino acids, fatty acids and glucose from the environment. However, the role of intracellular pathways of amino acid biosynthesis in T cell activation is relatively unexplored. Asparagine (Asn) is a non-essential amino acid that can be synthesized intracellularly through the glutamine-hydrolyzing enzyme asparagine synthetase (ASNS). We set out to define the requirements for uptake of extracellular Asn and ASNS activity in CD8+ T cell activation. At early timepoints of activation in vitro, CD8⁺ T cells expressed little or no ASNS and, as a consequence, viability and TCR-stimulated growth, activation and metabolic reprogramming were substantially impaired under conditions of Asn deprivation. At later timepoints (>24h of activation), TCR-induced mTOR-dependent signals resulted in upregulation of ASNS, that endowed CD8⁺ T cells with the capacity to function independently of extracellular Asn. Thus, our data suggest that the coordinated upregulation of ASNS expression and uptake of extracellular Asn is involved in optimal T cell effector responses.

Coordination of asparagine uptake and asparagine synthetase expression modulates CD8⁺ T cell activation

Helen Carrasco Hope,¹ Rebecca J. Brownlie,¹ Christopher M. Fife,¹ Lynette Steele,¹ Mihaela Lorger,¹ and Robert J. Salmond²

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Coordination of asparagine uptake and asparagine synthetase expression modulates CD8+ T cell activation

Helen Carrasco Hope,1 Rebecca J. Brownlie,1 Christopher M. Fife,1 Lynette Steele,1 Mihaela Lorger,1 and Robert J. Salmond2

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Coordination of asparagine uptake and asparagine synthetase expression modulates CD8⁺ T cell activation

Helen Carrasco Hope,¹ Rebecca J. Brownlie,¹ Christopher M. Fife,¹ Lynette Steele,¹ Mihaela Lorger,¹ and Robert J. Salmond²