Food for thought: Nutrient metabolism controlling early T cell development

Abstract

T cells develop in the thymus by expressing a diverse repertoire of either αβ- or γδ-T cell receptors (TCR). While many studies have elucidated how TCR signaling and gene expression control T cell ontogeny, the role of nutrient metabolism is just emerging. Here, we discuss how metabolic reprogramming and nutrient availability impact the fate of developing thymic T cells. We focus on how the PI3K/mTOR signaling mediates various extracellular inputs and how this signaling pathway controls metabolic rewiring during highly proliferative and anabolic developmental stages. We highlight the role of the hexosamine biosynthetic pathway that generates metabolites that are utilized for N- and O-linked glycosylation of proteins and how it impacts TCR expression during T cell ontogeny. We consider the dichotomy in metabolic needs during αβ- versus γδ-T cell lineage commitment as well as how metabolism is also coupled to molecular signaling that controls cell fate.

Keywords: PI3K/mTOR signaling; glycosylation; hexosamine biosynthesis; mTORC1/mTORC2; nutrient metabolism; thymic T cell development; αβ‐ and γδ‐T cells.

FIGURE 1

The development of αβ‐ and γδ‐T cells in the thymus. Early thymic progenitors lacking CD4, CD8 (double negative; DN) expression can be divided into DN1, DN2 and DN3 stages. At the DN2 stage and early DN3a, thymocytes begin to commit to the T lineage, marked by the rearrangement of the TCR chain loci. Divergence of lineages αβ versus γδ are likely complete by the DN3b stage. The level of expression of cell surface proteins including the TCR chains, co‐receptors and cytokine receptors (degree of expression is indicated by color gradient and triangular shape) serve as markers for specific stages. Metabolic pathway activity is indicated by color gradient, with darker shade representing more activity.

FIGURE 2

The PI3K/mTOR signaling pathway during early T cell development. During the highly proliferative stages of thymocyte development, PI3K and mTORC1/mTORC2 signaling are required to promote anabolic metabolism to ensure the presence of sufficient metabolites. PI3K mediates signals from Notch1, IL7‐R, CXCR4, and the pre‐TCR/TCR. How mTORC1 could itself be modulated by these signals remains unclear. mTORC2 and its substrate, Akt, also mediate signals from Notch1, IL7‐R, CXCR4, and the pre‐TCR/TCR and are required for proliferation and cell survival.

FIGURE 3

The hexosamine biosynthesis pathway (HBP) produces the metabolite, UDP‐GlcNAc, that is used for N‐ and O‐glycosylation of proteins, lipids and nucleic acids. The de novo synthesis of UDP‐GlcNAc is catalyzed by GFAT, which utilizes glutamine and the glycolysis metabolite, fructose‐6‐phosphate, to produce glucosamine‐6‐phosphate. Metabolites from the TCA cycle (acetyl‐CoA) and pyrimidine biosynthesis (UTP) are also utilized by the HBP to produce UDP‐GlcNAc. Salvage metabolites, such as glucosamine (GlcN) and N‐acetyl‐glucosamine (GlcNAc) can also be used to produce UDP‐GlcNAc.