Importance of AMP-activated protein kinase (AMPK) in the regulation of TGF-β pathway and T regulatory cells differentiation

Author(s)

Cesar Augusto Speck Hernandez

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2021-09-23

Examining board members

José Carlos Farias Alves Filho; Alexandre Salgado Basso; Leandro Machado Colli; Luiz Osório Silveira Leiria

• Advisor: José Carlos Farias Alves Filho

Abstract

Regulatory T cells (Tregs) are crucial components in maintaining peripheral immunotolerance and modulating the chronic inflammatory response. The transforming growth factor beta (TGF-β) is one of the cytokines responsible for the differentiation of Tregs, inducing the expression of the transcription factor FOXP3, which is considered the main regulator of genes associated with the differentiation and function of these cells. The AMP-activated protein kinase (AMPK) is a sensor of the cellular metabolic state that is activated when there is an increase in the intracellular AMP/ATP ratio. Through phosphorylation of target proteins, AMPK promotes the inhibition of anabolic pathways, such as protein synthesis, and stimulation of catabolic pathways, such as glycolysis, restoring metabolic balance. Interestingly, AMPK also regulates signaling pathways that are not directly associated with energy metabolism. In this context, it was demonstrated in fibroblasts that AMPK inhibits the TGF-β signaling pathway by phosphorylating Smads complex proteins, blocking their translocation to the nucleus. For this reason, we investigated the role of AMPKα in Treg cell differentiation. After treatment with TGF-β, AMPKα activity was reduced, promoting Foxp3 expression and subsequent Treg differentiation. The specific deletion of AMPKβ in T cells potentiates the TGF-β signaling pathway by increasing Smad2/3 phosphorylation and further increasing Foxp3 expression. AMPKα-deficient Treg cells not only differentiate more, but in turn produce more suppressor molecules. These cells are accompanied by metabolic changes that are characterized by decreased glycolytic metabolism, increased respiration and mitochondrial activity, increased protein glycosylation, and less proliferation. AMPKα-deficient Treg cells are stable and functional, and in a tumor development model, they have been shown to generate an immunosuppressive environment that favors tumor growth. These results together show that the differentiation of Treg cells depends on an energy balance that will control the needs of the cells based on the molecule signals that activate them. (AU)

• FAPESP's process: 18/23168-8 - Importance of AMP-activated protein kinase (AMPK) in the regulation of TGF-beta pathway and T regulatory cells differentiation
• Grantee: Cesar Augusto Speck Hernandez
• Support Opportunities: Scholarships in Brazil - Doctorate