Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) at the interface between mitochondrial activity, regulatory T cell biology and Cancer

• Grant number: 22/10585-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2023
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: José Carlos Farias Alves Filho
• Grantee: Luis Eduardo Alves Damasceno
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Company: Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE)
• Associated research grant: 21/00408-6 - Center for Research in Immuno-Oncology (CRIO), AP.PCPE

Abstract

Regulatory T (Treg) cells play important role in the maintenance of immunologic tolerance and control of immune responses. The transcription factor Foxp3 is essential for the development, stability and suppressive function of Treg cells. In the last few years, it has been evidenced different metabolic pathways driving the phenotype of Treg cells, which require mitochondrial integrity and metabolism for exerting their functions. Mitochondria are sites of biochemical processes including lipid oxidation, tricarboxylic acid cycle and oxidative phosphorylation, that culminate in generation of energy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) acts as an important regulator of oxidative metabolism, biogenesis and mitochondrial dynamics through the activation of different transcription factors, being widely described in tissues with high energy demand. Although a low expression of PGC1a has been related to the exacerbation of inflammatory responses, little is known about its intrinsic role in immune cells, especially in immunoregulatory functions. Our preliminary results demonstrate that Treg cells show a substantial increase in the expression of this transcription cofactor. Furthermore, the activation of PGC1a promotes an increase in the expression of Foxp3, which is reduced by its inhibition, suggesting a contribution of PGC1a in the development of Treg cells. Taking into account the relevance of PGC1a in the regulation of mitochondrial activity and integrity, in addition to the importance of oxidative metabolism for Treg cell function, this project aims to investigate how PGC1a connects the regulation of cellular metabolism to the generation and function of Treg cells in homeostasis and tumor context. (AU)