T cell activation, differentiation and effector function is intrinsically linked to the regulation of metabolic pathways. Evidence has shown that inflammatory T cell responses are dependent upon the adoption of aerobic glycolytic metabolism. Furthermore, activation and regulation of the mechanistic target of rapamycin signaling pathway serves a key determinant of T cell metabolism, with subsequent effects on T cell effector responses. In this mini-review, we discuss the mechanisms underpinning the function of the Warburg effect in T cell responses and the role of mTOR in these processes.

T cell receptor (TCR) triggering by antigen results in metabolic reprogramming that, in turn, facilitates the exit of T cells 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 is a nonessential 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 asparagine and ASNS activity in CD8 ⁺ T cell activation. At early time points 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 asparagine deprivation. At later time points (more than 24 hours of activation), TCR-induced mTOR-dependent signals resulted in ASNS upregulation that endowed CD8 ⁺ T cells with the capacity to function independently of extracellular asparagine. Thus, our data suggest that the coordinated upregulation of ASNS expression and uptake of extracellular asparagine is involved in optimal T cell effector responses.

T cell activation, differentiation and proliferation is dependent upon and intrinsically linked to a capacity to modulate and adapt cellular metabolism. Antigen-induced activation stimulates a transcriptional programme that results in metabolic reprogramming, enabling T cells to fuel anabolic metabolic pathways and provide the nutrients to sustain proliferation and effector responses. Amino acids are key nutrients for T cells and have essential roles as building blocks for protein synthesis as well as in numerous metabolic pathways. In this review, we discuss the roles for uptake and biosynthesis of non-essential amino acids in T cell metabolism, activation and effector function. Furthermore, we highlight the effects of amino acid metabolism and depletion by cancer cells on T cell anti-tumour function and discuss approaches to modulate and improve T cell metabolism for improved anti-tumour function in these nutrient-depleted microenvironments.

Transforming growth factor β (TGFβ) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8⁺ T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity, helps Ptpn22 ^−/− T cells to be intrinsically superior at clearing established tumors that secrete TGFβ. Mechanistically, loss of Ptpn22 increases the capacity of T cells to produce IL-2, which overcomes TGFβ-mediated suppression. These data suggest that a viable strategy to improve anti-tumor adoptive cell therapy may be to engineer tumor-restricted T cells with mutations identified as risk factors for autoimmunity.

Adoptive T cell therapy (ACT) has been established as an efficacious methodology for the treatment of cancer. Identifying targets to enhance the antigen recognition, functional capacity, and longevity of T cells has the potential to broaden the applicability of these approaches in the clinic. We previously reported that targeting expression of phosphotyrosine phosphatase, nonreceptor type 22 (PTPN22) in effector CD8 ⁺ T cells enhances the efficacy of ACT for tumor clearance in mice. In the current work, we demonstrate that, upon ACT, PTPN22-deficient effector CD8 ⁺ T cells afforded greater protection against tumors expressing very low-affinity antigen but did not survive long term in vivo. Persistence of CD8 ⁺ T cells following tumor clearance was improved by ACT of memory phenotype cells that have a distinct metabolic phenotype, as compared with effector T cells. Importantly, PTPN22-deficient T cells have comparable capacity to form long-lived memory cells in vivo but enhanced antitumor activity in vivo and effector responses ex vivo. These findings provide key insights into the regulation of effector and memory T cell responses in vivo and indicate that PTPN22 is a rational target to improve ACT for cancer.