Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells

Abstract

To fulfil the bioenergetic requirements for increased cell size and clonal expansion, activated T cells reprogramme their metabolic signatures from energetically quiescent to activated. However, the molecular mechanisms and essential components controlling metabolic reprogramming in T cells are not well understood. Here, we show that the mTORC1–PPARγ pathway is crucial for the fatty acid uptake programme in activated CD4+ T cells. This pathway is required for full activation and rapid proliferation of naive and memory CD4+ T cells. PPARγ directly binds and induces genes associated with fatty acid uptake in CD4+ T cells in both mice and humans. The PPARγ-dependent fatty acid uptake programme is critical for metabolic reprogramming. Thus, we provide important mechanistic insights into the metabolic reprogramming mechanisms that govern the expression of key enzymes, fatty acid metabolism and the acquisition of an activated phenotype during CD4+ T cell activation.

HIV Persistence in Adipose Tissue Reservoirs

“…Activation of mTOR, a major regulator of metabolic pathway utilization and T cell activation, was recently demonstrated by Besnard et al to be essential for induction of latent HIV in human CD4 T cells [120]. Rasheed et al showed that HIV replication upregulates lipid metabolism pathways and production of free fatty acids in infected human CD4 T cells, and consistent with this study, Angela et al showed that fatty acid metabolism through mTOR and PPARγ activation is critical for maximal activation of human CD4 T cells [121, 122]. CD4 T regulatory cells, important regulators of adipose tissue homeostasis as well representing a cellular reservoir for latent HIV, preferentially utilize oxphos and recent studies have demonstrated that Foxp3 promotes activation of oxphos and fatty acid oxidation pathways [123–126].…”

Fatty acid metabolism in CD8+ T cell memory: Challenging current concepts

“…Glucose is not the only nutrient used by T n cells, which can also oxidize external lipids like oleate and palmitate in their mitochondria (23, 24). To this end, T n cells express enzymes that support the oxidation of long-chain fatty acids (LCFAs) (25), and metabolomic analysis of these cells found abundant acylcarnitine molecules, which correlate with this process (24, 26). …”

Metabolic abnormalities and oxidative stress in lupus

“…Lipids and fatty acids are also critical nutrients for lymphocytes; not only are they integral components of cell membranes, but they are also a high energy source [21,22]. To date, the overarching theme in lymphocyte metabolism is that, as opposed to the glycolytic phenotype of activated effector T cells, memory and regulatory T cells can also metabolize amino acids and fatty acids, and generate ATP through OXPHOS.…”