CD8+ T cell metabolic rewiring defined by scRNA-seq identifies a critical role of ASNS expression dynamics in T cell differentiation

Asparagine availability controls B cell homeostasis

“…This corresponded with a preference for uptake of extracellular Asn, which was greatly increased following activation. Initial stimulation with Asn provided a protective effect against subsequent Asn withdrawal, as also observed in CD8 + T cells 11,32 , which we found was mediated in part by upregulation of ASNS, which was almost undetectable in naïve B cells. The residual survival benefit observed in pre-stimulated B-Asns cells may be mediated by cellular reserves of Asn, or by a lower requirement for Asn once activation has occurred, and this is supported by our finding that deprivation of Asn substantially impairs B cell activation.…”

“…Amino acid availability is a critical regulator of T cell responses, demonstrated either by alteration of environmental abundance, synthesis, or interference with cellular import through solute transporters [9][10][11][12][13][14][15] . Amino acids are fundamentally required for protein synthesis, but are central to other metabolic processes 16 , and it is apparent in T cells that availability of specific amino acids can have profound effects on their homeostasis.…”

In silicosingle-cell metabolism analysis unravels a new transition stage of CD8 T cells 4 days post-infection

“…In this study we have made use of the scFEA algorithm (Alghamdi et al, 2021) to evaluate at the single-cell level the global metabolic activity in CD8 T cells responding to a viral infection in vivo from scRNA-seq data (Kurd et al, 2020;Milner et al, 2020). Previous single-CD8-Tcell metabolic analyses relied only on scRNA-seq measurements of mRNA levels of in vitro activated cells (Fernández-García et al, 2022), or cytometry quantification of a few selected p. 9 proteins implied in metabolism and/or its regulation (Ahl et al, 2020;Hartmann et al, 2021;Levine et al, 2021). However, mRNA and protein levels are not linearly correlated to the activity of the corresponding metabolic modules and our study is the first attempt at globally evaluating all metabolic activities in single responding CD8 T cells.…”

“…However, effector and memory CD8 T cell populations are heterogeneous (Appay et al, 2002; Kaech and Cui, 2012; Mittrücker et al, 2014) and different subsets shall undergo and require specific metabolic programs (Geiger et al, 2016; Gupta et al, 2019). Thus, an analysis of the metabolism of CD8 T cell responding to a viral infection at the single-cell level would be much more biologically relevant (Arsenio et al, 2014; Ahl et al, 2020; Fernández-García et al, 2022). However, single-cell metabolomic techniques still suffer from relatively low throughput and sensitivity (Duncan et al, 2019; Sengupta et al, 2019).…”

Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity

“…The impact of asparagine on T‐cell differentiation depends on its ability to function as a mammalian target of the rapamycin complex (mTORC1) activator, thus dynamically controlling mTORC1 and regulating cellular mitotic spindle formation 60,61 . However, the timing of asparagine depletion is regulated by ASNS overexpression during the predifferentiation stage in CD8+ T cells, which prompts Tcm polarisation and early differentiation, resulting in a delay in Tcm polarisation and driving T‐cell differentiation towards T cells with effector phenotypes 53 . Furthermore, Tscm synthesis depends on the relationship between metabolic activity and Wnt‐catenin/glycogen synthase kinase‐3/mTORC1 signalling 62 .…”